gp130 CYTOKINE FAMILY AND BONE CELLS

doi:10.1006/cyto.2000.0747, available online at http://www.idealibrary.com on

REVIEW ARTICLE

gp130 CYTOKINE FAMILY AND BONE CELLS Dominique Heymann1,2* and Anne-Vale´rie Rousselle1 Bone tissue is continually being remodelled according to physiological circumstances. Two main cell populations (osteoblasts and osteoclasts) are involved in this process, and cellular activities (including cell differentiation) are modulated by hormones, cytokines and growth factors. Within the last 20 years, many factors involved in bone tissue metabolism have been found to be closely related to the inflammatory process. More recently, a cytokine family sharing a common signal transducer (gp130) had been identified, which appears to be a key factor in bone remodelling. This family includes interleukin 6, interleukin 11, oncostatin M, leukaemia inhibitory factor, ciliary neurotrophic factor and cardiotrophin-1. This paper provides an exhaustive review of recent knowledge on the involvement of gp130 cytokine family in bone cell (osteoblast, osteoclast, etc.) differentiation/activation and in osteoarticular pathologies.  2000 Academic Press

Bone is a specialized connective tissue that, together with cartilage, makes up the skeleton system. Bone tissue has various functions, including mechanical properties (offering the site and support for muscle tissue insertion for locomotion), protective properties for vital organs (lung, heart, brain, bone marrow, etc) and a metabolic role (bone is the main reserve of ions for the organism, especially calcium and phosphate). Bone tissue results from the activities of many cell lineages, including mainly osteoblasts, osteocytes and osteoclasts. Osteoclasts are multinucleated cells that possess several characteristic features, such as a highly polarized morphology, apical differentiation adjoining the calcified matrix in resorption (known as the ‘‘ruffled border’’), and numerous mitochondria (Fig. 1A). Osteoblasts are bone-forming cells (Fig. 1B) which are progressively transformed into osteocytes (Fig. 1C, D) imprisoned in their own secretion products which form lacunae after mineralization. From the 1Laboratoire de Physiopathologie de la Re´sorption Osseuse, EE 99-01, Faculte´ de Me´decine, 1 rue Gaston Veil, 44035 Nantes cedex 1, France; 2Laboratoire d’Histologie et Embryologie, Faculte´ de Me´dicine, Nantes cedex 01, France *Correspondence to: Dominique Heymann. E-mail: [email protected] Received 22 March 2000; accepted for publication 22 March 2000  2000 Academic Press 1043–4666/00/101455+14 $35.00/0 KEY WORDS: gp130/IL-6/IL-11/leukaemia inhibitory factor/ciliary neurotrophic factor/oncostatin M/ cardiotrophin-1/bone/ osteoblast/osteoclast Abbreviations used: CNTF: ciliary neurotrophic factor; CT-1: cardiotrophin-1; gp: glycoprotein; IL: interleukin; LIF: leukaemia inhibitory factor; OSM: oncostatin M CYTOKINE, Vol. 12, No. 10 (October), 2000: pp 1455–1468

These cells, which have an extensive endoplasmic reticulum and numerous free ribosomes in the cytoplasm, are connected by gap junctions. Secondary cell types such as monocytes/macrophages and endothelial cells also contribute to the bone remodelling by direct contact with osteogenic cells or by the release of soluble factors (cytokines, growth factors). In 1969, Frost showed that osteoblasts and osteoclasts are closely associated in time and space.1 Thus, after receiving a bone stimulus (i.e. mechanical load, hormones, growth factors) from the lining, osteoblastic and osteoclastic cells appear on the bone surface and resorb the mineral components of bone by an acid extracellular mechanism.2–4 Osteoblastic cells stimulated by osteoclastic contacts and/or osteoclastic soluble factors deposit osteoid on the resorption site, initiating bone formation.5 Osteoblasts not only initiate but also control bone mineralization. Although all osteogenic cells (osteoblasts, osteoclasts) contribute individually to bone remodelling, their cellular interactions control cellular activities and the intensity of bone remodelling. These interactions can be established through cell–cell contact, 6 which may involved molecules from the integrin family 7 or the release of many polypeptidic factors and/or their soluble receptor chains.8–10 These factors can act directly on osteogenic cells on their precursors and control differentiation, formation and functions (matrix formation, mineralization, resorption, etc.). Among the known soluble polypeptide factors, a pleiotropic cytokine family sharing a common signal 1455

1456 / Heymann and Rousselle

Figure 1.

CYTOKINE, Vol. 12, No. 10 (October, 2000: 1455–1468)

Ultrastructural morphology of the three main cell types of bone tissue.

(A) Human osteoclasts obtained from a patient with giant-cell tumour and cultured on dentine slices. Arrowhead: dentine; arrow: resorption lacunae; asterisk: ruffled border; original magnification5000; bar: 4
m. (B) Murine osteoblast on the mineralization front; arrowhead: mineral phases of bone surface; arrow: extensive mineralization on collagen fibres; original magnification7300; bar: 1
m. (C) Murine osteoblast progressively imprisoned in the mineral phase (arrowhead). Arrow: canaliculi containing cytoplasmic processes; original magnification5000; bar: 1
m. (D) Murine osteocytes enclosed in lacunae (arrowhead) formed in dense mineralized areas (arrow); *: mineral phases of bone; original magnification5000; bar: 1
m.

transducer (gp130)11 plays a key role during bone remodelling. This family includes cardiotrophin-1, CNTF, IL-6, IL-11, LIF and OSM, which all show structural similarities (amino acid sequence, threedimensional structure) and produce similar activities on a variety of target cells, including haematopoietic cells, hepatocytes, neurons, embryonic stem cells and bone cells.12–20 This review will focus on the involvement of gp130 cytokine family (cardiotrophin-1, CNTF, IL-6, IL-11, LIF, OSM) on the formation and functions of osteogenic cells (osteoblasts, osteoclasts). An overview will be provided of the potential implication of these cytokines during osteoarticular pathologies.

Leukaemia inhibitory factor (LIF), oncostatin M (OSM) and bone cells

LIF and OSM are clearly related cytokines whose genes are located on chromosome 22q12 distal to the Ewing’s sarcoma break-point and within 500 kb of each other.21 Moreover, OSM can mimic LIF activities both in vitro and in vivo and shares common gp130 and gp190 transducing receptor subunits with LIF, accounting in part for their redundancy.21–25 LIF is produced by numerous cell types, including lymphocytes,26 monocytes,27 bone-marrow stromal28–30 and osteoblastic cells.31,32 Malignant cells also express LIF cytokine.33,34 LIF produced by osteogenic cells and mesenchymal cells is regulated by key molecules

gp130 cytokine family and bone cells / 1457

involved in bone metabolism, such as PTH and PTHrP.31 Moreover, Pollock et al. have shown that both LIF and IL-6 are physiologically important mediators of at least some actions of PTH and PTHrP.31,35 OSM production is generally restricted to haemopoietic cells, and no production by osteogenic cells has yet been detected.36–38 The first evidence of LIF activities during bone remodelling steps was provided by Metcalf and Gearing, who showed that mice engrafted with LIFcDNA transfected cells producing high amounts of LIF developed a fatal syndrome within 12–70 days characterized by cachexia, excessive new bone formation and ectopic calcifications in skeletal muscles and heart.39,40 The effect of LIF and OSM on bone remodelling may be mediated by osteoblasts and bone-marrow stromal cells which, unlike osteoclasts, express receptors for both.24,41–43 However, the activity of LIF and the presence of LIF receptor chain (gp190) have recently demonstrated in osteoclast-like cells cultured from human giant-cell tumour of bone.44,45 Nonetheless, LIF and OSM stimulated osteoclast-like cell formation and resulting resorption mechanisms when bone-marrow cells were co-cultured in vitro in the presence of osteoblasts.46 Their receptors are active on osteoblastic cells and transduce the signal via protein phosphorylations (tyrosine kinase47–51 and non-tyrosine kinase52 pathways). At the present time, osteoblasts appear to be the main target of LIF and OSM and could act indirectly on osteoclasts via the release of prostaglandins.53–55 IL6-type cytokines (LIF, OSM, IL-6) that utilize the gp130 signal transducer are potent anti-apoptotic agents on osteoblastic cell types (MC3T3-E1 and MG-63).56 Thus, these cytokines like TGF- are able to counteract the effect of serum starvation or TNF. The induction of apoptosis in human MG-63 cells is associated with an increase in the ratio of the pro-apoptotic protein bax to the anti-apoptotic protein bcl-2, whereas oncostatin M prevents this change. LIF and OSM also influence the differentiation/proliferation system of osteoblasts. The effects of LIF on the proliferation of osteoblastic cells are reported to have a stimulatory or inhibitory effect (depending on the model used, on the age of the animals and the site).57–63 If LIF and OSM can modulate the differentiation/proliferation system, they can also influence the physicochemical characteristics of the bone mineral formed (i.e. ionic microenvironment, etc.). Such variations have been observed in a murine heterotopic calcification model,64 where LIF and OSM increased the number of bone-marrow stromal cell progenitors with osteogenic potential.65 In this model, both cytokines induced an immature state of the mineral deposited on the extracellular matrix, as revealed by the presence of environment rich in labile non-apatitic phosphate, carbonate and

HPO4.66 Similar results have been obtained in in vitro rat bone-marrow stromal cell cultures.67 The effect of LIF and OSM on osteoclastic activation and resorption are not so clear. Thus, Turner et al. analysed the effects of injected LIF in growing rats and have observed that high systemic concentrations of LIF resulted in hypercalcaemia with no changes in bone turnover.68 LIF and OSM increased the amounts of mineral deposited in these various models, but also modified the quality of the mineral, which is one of the key parameters regulating the resorption mechanism induced by osteoclasts.69 Although both cytokines can influence mineral phases and osteoclast activities, no direct action on these cells has yet been demonstrated, essentially because of the difficulties in obtaining a pure population of osteoclasts. However, numerous data have reinforced the potential role of both cytokines in resorption mechanisms.43–46,70–72 For example, in vitro exposure of human long-term bone-marrow culture to recombinant human LIF and OSM significantly increased the number of multinucleated cells formed after three weeks of culture.73,74 The multinucleated cells formed expressed the macrophage polykaryon phenotype and were capable of low-grade resorption in the presence of bone-marrow stromal cells. OSM reduced the resorption induced by these cells. OSM and LIF could thus modulate bone remodelling toward such mechanisms (orientation of bone-marrow mononuclear cell differentiation to macrophage polykaryon phenotype). These results are in agreement with those obtained by Sarma and Flanagan, who showed that LIF did not increase bone resorption but upmodulated 23c6positive cells (an antibody that recognizes the vitronectin receptor, which is one of the characteristics of osteoclasts) in a human bone-marrow mononuclear cell fraction co-cultured with human bone-marrow stromal cells.75 Moreover, Benahmed et al. found that LIF inhibits the differentiation of monocytes into macrophages and their ability to manifest macrophagic activity.76 Similarly, Sabokbar et al. have shown that LIF, like IL-4, inhibits the osteoclastic differentiation (tartrate-resistant acid phosphatase activity and lacunar bone resorption) from monocyte co-cultured with osteoblast-like cells in presence of polymethylmethacrylate wear particules.77 Numerous proteinases produced by bone cells (osteoblasts, osteoclasts) contribute to bone remodelling. Thus, the prevention of bone resorption by collagenase and/or gelatinase inhibitors or by cysteine inactivators has provided direct evidence for the participation of cysteine proteinases and matrix metalloproteinases in bone resorption. Varghese et al.78,79 have demonstrated that LIF and OSM stimulates collagenase-3 (MMP-13) and tissue inhibitors of metalloproteinase-1 (TIMPs) expression in osteoblasts,

1458 / Heymann and Rousselle

but do not regulate the expression of gelatinase A (MMP-2), B (MMP-9), TIMP-2 and TIMP-3 in primary cultures of osteoblast-enriched cells isolated from fetal rat calvaria.80 These results are in agreement with those obtained by Damiens et al. (personal communication) in osteoblastic type cells such as SaOS2 or MG-63,81 and those of Cowell et al. who showed that OSM upmodulated collagenase-3 expression in chondrosarcoma cells.82 Various transgenic or knockout mice have been developed to determine the real involvement of LIF and OSM in bone remodelling.83–88 Bone metabolic evidence is suggested by data obtained from chronic overproduction of LIF following the introduction of LIF transgenes.39,40 Shen et al. generated a transgenic mouse line that expressed diffusible LIF protein in T cells.83 No abnormalities in bone growth appear to have been detected in this study. However, the limited overproduction of LIF protein by T cells made the evaluation of LIF effects difficult. Escary et al.84 as well as Stewart et al.85 have developed LIF-deficient mice derived by gene-targeting techniques. Their model indicates that transient expression of LIF in mice is essential for blastocyte implantation and maintenance of haematopoietic stem cells and thymocyte stimulation. They also observed that viable homozygous mice deficient in LIF expression had a retarded postnatal growth rate (body weight 25–35% smaller). However, no specific analysis of bone tissue was performed in their studies. In transgenic mice overexpressing OSM, Malik et al. observed that the animals developed osteopetrotic bone tissue, possibly by stimulation of bone formation and inhibition of bone resorption.84 As the effects of both cytokines can be redundant with those of IL-6, IL-11, CT-1 and CNTF, gp130 gene knockout mice and gp190 gene knockout mice have been generated.87,88 Kawasaki et al. compared bone tissue from gp130-deficient and wild-type newborn mice87 and observed a decrease in trabeculae at the metaphysical region in tibia and radii of deficient mice as well as an increase in the number of osteoclasts. No apparent differences were noted in the distribution of alkaline-positive osteoblasts and the osteoid surface on trabecular bone of the metaphysical region, whereas the volume of mineralized trabecular bones was decreased at mandibulae. These data confirm the role of gp130 cytokine family during bone remodelling, but also indicate that osteoclast formation is not solely dependent on gp130 signalling. These cytokines could have an inhibitory effect on osteoclastic formation, and the persistence of osteoclasts in gp130-deficient mice may be caused by the functional redundancy of bone-resorbing factors. Similarly, experiments performed with gp190-deficient mice88 showed that this defect induced a reduction of fetal bone volume. The decrease of osteoid volume associated with an increase

CYTOKINE, Vol. 12, No. 10 (October, 2000: 1455–1468)

of osteoclast number resulted in osteopenia of perinatal bone. These results confirm those obtained in gp130-deficient mice.

INTERLEUKIN 6 (IL-6), INTERLEUKIN 11 (IL-11) AND BONE CELL IL-6 and IL-11, like LIF, OSM, CT-1, and CNTF, are multifunctional cytokines16–19,89 which share the common receptor transducer gp130.11,20,48,90 A large number of cell types express IL-6 such as monocytes, fibroblasts, endothelial cells, chondrocytes, bonemarrow stromal cells, keratinocytes and bone cells.91 These large production sites correspond to numerous biological activities, such as functions in immune cells, haematopoiesis, acute phase response during inflammation, the neurological system and bone remodelling (see references92,93). The main source of IL-6 in bone is osteoblastic cells and stromal cells, and not osteoclastic type cells.94 IL-6 is produced by osteoblastic-type cells and bone-marrow stromal cells and is modulated by various agents (Tri-iodothyronine, IL-13, sphingosine, retinoic acid, prostaglandins, oestradiol, basic FGF, TNF, etc.)93,95–103 and in specific conditions such as gravity.104 IL-11 was originally discovered as a crossreacting cytokine in an IL-6 bioassay.105 IL-11 gene is expressed in a variety of normal and cancer cells of mesenchymal origin (bone-marrow stromal cells, lung, uterus, connective tissues, skin, testis, etc.) and is modulated by several inflammatory cytokines and agonists as well as hormones.90 Primary human osteoblasts produce a very low amount of IL-11, which is strongly upmodulated by TGF-1.106–108 IL-11 is also produced by bone-marrow stromal cells and modulated by osteotropic agents. Thus, its production is stimulated by IL-1, PTH, basic FGF, and inhibited by interferon-.109–112 IL-11 act synergistically with other cytokines (IL-3, IL-4, IL-13, stem cell factor, etc.) to stimulate various haemopoietic stages and lineages. Thus, IL-11 stimulates the proliferation of primitive stem cells. The other main activities concern its effects on epithelial cells (inhibition of proliferation), neurogenesis (stimulation of the proliferation of hippocampal neuronal cells), inflammation (stimulation of acute phase reactants; see reference90). These results indicate that appropriate osteoblastic cells and bone-marrow stromal cells are potent producers of IL-6 and IL-11, which may be important components of the cytokine network mediating bone cell communications during bone remodelling. Although osteoblastic cells express IL-6 mRNA and produce the protein, they apparently do not respond to this factor.113,114 Few data have concerned the effects of IL-6 on osteoblastic cells. ‘‘High’’ concentrations of IL-6 (>10 ng/ml) were found to produce a slight increase in tritiated thymidine in the

gp130 cytokine family and bone cells / 1459

UMR-106-01 tumour cell line.115 Like LIF and OSM, IL-6 is a potent anti-apoptotic agent on osteoblastic cells via transcriptional activation of the p21 gene.56,116 Moreover, IL-6-type cytokines stimulate mesenchymal progenitor differentiation toward the osteoblastic lineage.117 However, Hughes et al. have shown that IL-6 inhibits bone formation118 in vitro, which suggests that studies on the quality of the mineral phases formed in presence of IL-6 could be crucial in determining the real impact of this cytokine on bone formation. The main activity of IL-6 on bone is its effect on osteoclastogenesis and bone resorption. Thus, Kuhihara et al. showed that IL-6 stimulates osteoclastlike formation in long-term human marrow culture by IL-1 release, whereas the addition of anti-IL-1 inhibits the increase in osteoclast formation induced by IL-6.119 IL-6 also mediates the same stimulatory effects as TNF120 and PTH.121 These data, which have been confirmed in vivo122 and depend on the model used.123 IL-6 also enhances PTHrp-mediated hypercalcaemia and bone resorption, by increasing the pool of osteoclastic progenitors and then after differentiation of mature osteoclasts.124 In a murine model, IL-6 strongly increases the formation of multinucleated cells only in the presence of IL-6 soluble receptor gp130.47 Flanagan et al. demonstrated, using a model of human bone-marrow stromal cells recharged with non-adherent bonemarrow cells, that IL-6 failed to induce a similar stimulatory effect.125 In this study, IL-6 was not able to replace the stromal factor(s) required for the formation of cells capable of resorbing bone. These authors concluded that IL-6 is not critical in stimulating osteoclastic bone resorption. IL-6 and LIF similarly had no effect in a murine model.126 This discrepancy can be explained by the fact that the exact nature of these cells, referred to by some authors as ‘‘osteoclast-like’’, remains controversial (osteoclasts or macrophagepolykaryons?).10 Curiously, IL-6 produced by osteoblasts in response to CD34 + haematopoietic bone-marrow cells127 which are able to differentiate in osteoclasts under specific conditions.128 In this case, what is the real involvement of IL-6 in the dichotomic system: osteoclast and haematopoietic differentiation? The effect of IL-6 on osteoclasts in human bone marrow has been analysed recently by stromal cells transfected by a cDNA coding for human IL-6 and injected into human bone implants implanted in NOD/ SCID mice.129 These data demonstrate that only implants engrafted with IL-6/stromal cells had an upmodulation in osteoclast-lined mineralized trabecular bone surface. Similarly, in the human giant-cell tumour model, IL-6 antisense deoxyoligonucleotides inhibit bone resorption by these osteoclast-like cells.130 IL-6 produced by these tumours may then be involved in the autocrine induction of osteolysis, which is associ-

ated with biologic aggressiveness.131 IL-6 exerts its activities via a cell-surface receptor which consists of two glycoproteins, gp80 and gp130. When gp80 is occupied by IL-6, this complex binds to gp130 and transduces IL-6 signals. In this context, various studies have analysed the expression of these receptors to determine the target cells of IL-6 during osteoclastic differentiation/activation.132,133 Thus, Udagawa et al. have demonstrated that induction of osteoclast differentiation by IL-6 is dependent on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors.132 Tamura et al. showed that neither recombinant IL-6 nor soluble IL-6 receptor (gp80) induced osteoclast-like formation from mouse bonemarrow cells. Conversely, addition of IL-6 and IL-6soluble receptor induced osteoclast-like formation.46 However, these apparently contradictory results were mainly due to the differentiation level of bone tissue used and to methodological differences. More recently, Gao et al. showed that gp130 and IL-6 receptors are expressed on tartrate-resistant acid phosphatasepositive mononuclear cells and isolated murine osteoclasts. In this model, IL-6 caused enhancement of the resorbing activity in a dose-dependent manner, indicating the involvement of IL-6 in the formation and activation of osteoclasts.132 The presence of IL-6 receptors on osteoclast membrane has been confirmed by confocal microscopy and by in situ reverse transcriptase PCR histochemistry.133 Adebanjo et al. also found that IL-6, but not IL-11, reverses the inhibition of osteoclastic bone resorption induced by high extracellular Ca2+ and may sustain osteoclastic activity versus an inhibitory Ca2+ level generated locally during resorption.134 The importance of the IL-6 function during bone remodelling has been confirmed in oestrogen-deficient animals.135,136 These studies indicate that ovariectomy does not induce any change in either bone mass or bone remodelling rates in the IL-6-deficient mice and that anti-IL-6 monoclonal antibodies inhibit upmodulation in osteoclast precursors occurring in oestrogen depleted mice. These results are in accordance with those obtained by Girasole et al. who demonstrated that ovariectomized animals display elevated serum levels of IL-6 that can be normalized by administration of oestradiol.99 However, though serum IL-6 levels increase with age, no correlation was found between bone turnover, ovarian function and serum IL-6 level in a study of 80 normal women (24–87 years of age).137 These results are not concordant with the study of Bismar et al.138 who found increased IL-6 levels in patients with postmenopausal osteoporosis. At the present time, the actual involvement of IL-6 in patients with postmenopausal osteoporosis is still unclear. Moreover, macaques injected with recombinant IL-6 showed no upmodulation of calcium release, thereby indicating that there

1460 / Heymann and Rousselle

is no modulation of bone resorption in vivo.139 Thus, there is still controversy about the candidate molecules that stimulate bone resorption during oestrogen depletion and subsequent osteoporosis. The protective effects of oestrogen for bone could involve two other candidates, namely TNF140 and/or IL-11.141 To complicate the various observations, Schiller et al. have observed that osteoclastogenesis induced by 1, 25 (OH)2D3 is partially dependent on IL-6 and is modulated by 17-oestradiol through interference IL-6 receptor activation as well as inhibition of IL-6 produced by bone-marrow stromal cells.100 IL-6 could also be an appropriate candidate during bone loss caused by androgen deficiency,142 insofar as 17oestradiol and dihydroxytestosterone decrease the expression of gp130 and gp80 in the murine bonemarrow cells.143 These studies have been supplemented by those of Nishida et al., who used a monoclonal antibody in normal and ovariectomized rats.144 Osteoclast-like cells, as well as osteoblasts, express IL-11 receptor transcripts and a sequential relationship exists between expression of the calcitonin receptor mRNA and IL-11 receptor mRNA.145 Gp130 signals, evoked by IL-11, are indispensable for IL-1-induced osteoclast formation. Further studies are required to elucidate the role of IL-11 in mature osteoclasts functional IL-11 receptors on osteoclasts (IL-11 does not influence by itself osteoclast survival and anti-gp130 antibody does not influence pit resorption by these cells).145 However, IL-11 upmodulated the formation of osteoclast-like cells from mouse bone-marrow cells,108,145–147 as well as the surface of calcified matrix resorbed by these cells which involves both metalloproteinases and products of achidonic acid metabolism.145,147 IL-11 has been implicated in oestrogen deficiency-induced bone loss. Thus, a neutralizing monoclonal antibody inhibited the osteoclastogenesis induced by 1, 25 (OH)2D3 and PTH in both normal and ovariectomized mice (IL-6 antibody was an inhibitor only in ovariectomized mice).108 Recent in vitro data also indicate that IL-11 production induced by PTH or IL-1 in human bone-marrow stromal cells was not modulated by 17-oestradiol109 and that injected recombinant IL-11 did not modify biochemical parameters of bone remodelling in adult ovariectomized rats.148 Moreover, IL-6 and IL-11, like LIF and OSM, can induce bone resorption by modulating proteinase release by bone cells.81,147,149 Transgenic or knockout mice have been developed to determine the real involvement of IL-6 in bone remodelling (Table 1). Thus downmodulation in osteoblasts and in osteoid, as well as a decrease in osteoclasts and bone resorption, has been observed predominantly in transgenic mice overexpressing IL-6. These modulations resulted in the suppression of bone turnover.150 Overexpression of IL-6 also induced

CYTOKINE, Vol. 12, No. 10 (October, 2000: 1455–1468)

plasmocytomas, indicating the potential involvement of this cytokine in myeloma pathology.151,152 The role of IL-6 during bone turnover was confirmed in IL-6deficient mice which showed an increase of bone turnover and were protected from bone loss caused by oestrogen depletion.136 Similar transgenic mice have been generated with IL-11, but no data are available concerning the quality of mouse bone, and bone turnover has not been studied.153,154

CARDIOTROPHIN-1 (CT-1) AND CILIARY NEUROTROPHIC FACTOR (CNTF) AND BONE CELLS Although considerable data have been published concerning the role of CT-1 and CNTF, particularly in muscular and nervous systems,13,14 no specific study has been performed concerning the effects of these cytokines on the bone system. Apparently, CNTF did not modify embryonic development and growth in CNTF gene knockout mice.14

gp130 CYTOKINE FAMILY AND OSTEOARTICULAR PATHOLOGIES The gp130 cytokine family is involved in osteoarticular pathologies, mainly in osteolytic diseases (giant-cell tumours, Paget’s disease, bone metastasis) and in rheumatoid arthritis. Thus, because of its involvement in bone remodelling and its expression by some tumours cells, LIF has been studied in vivo in human primary benign and malignant tumours.155 In this study, LIF was never detected in any sera tested, in control urine samples, or in supernatants from normal cancellous bone cultures. A high level of LIF was found in all supernatants from malignant tumour cultures (100%) and in supernatant from cultured benign tumours (86%). LIF levels were particularly high in supernatant from chondrosarcoma. Immunohistochemical analysis revealed that LIF is present in all benign endochondromas and malignant chondrosarcomas, but not in control tissue.156 The cytokine is localized in cartilage cells, and the number of stained cells ranges from less than 5% in endochondroma of the hand to more than 70% in high-grade chondrosarcoma. These studies raise the question of the significance of LIF in tumour-associated bone resorption and the potential role of this cytokine as a prognostic marker. The role of LIF during malignant osteolysis has been confirmed by Gouin et al., who found the presence of LIF receptors on osteoclast-like cells from human giant-cell tumours.44 Similarly, IL-6 could be involved during osteolysis induced by giant-cell tumours, as described by Reddy et al.130,157 Interleukin 6 antisense deoxyoligonucleotides inhibited bone

gp130 cytokine family and bone cells / 1461

TABLE 1.

Transgenic mice for the gp130 cytokine family and their receptor subunits: effects on bone tissue

Type of mice

Effects observed

Authors (references)

Transgenic mice overexpressing LIF in T lymphocytes

Normal growth

Shen et al.83

Trangenic mice overexpressing IL-6

Decrease in osteoblasts and osteoid, and decrease of both osteoclast number and bone resorption Plasmocytoma formation Suppression of bone turnover

Kitamura et al.149 Suematsu et al.150,151

Trangenic mice overexpressing OSM

Osteopetrotic bone (stimulation of bone formation and inhibition of bone resorption)

Malik et al.84

LIF gene knockout mice

Retarded postnatal growth rate

Escary et al.85 Stewart et al.86

IL-6 gene knockout mice

No significant change in osteoclast and osteoblast surfaces Increase of bone turnover

Poli et al.135

CNTF gene knockout mice

Normal embryonic development and growth

Sariola et al.14

gp130 gene knockout mice

Osteopenia (decrease in the amount of trabeculae at the metaphysical region in the tibia and radii) Increase of osteoclast number

Kawasaki et al.87

gp190 gene knockout mice

Reduction of fetal bone volume (severe osteopenia of perinatal bone) Decrease in osteoid volume Increase of osteoclast number

Ware et al.88

Targeted expression of IL-11 in mice

Not studied

Tang et al.152

Mice with targeted mutation of the IL-11 receptor

Not studied

Nandurkan et al.153

resorption by giant cells from human giant-cell tumours of bone, demonstrating the autocrine biological activity of IL-6 on osteoclasts. Several models inducing experimental bone metastasis158 have been used to study the role of the gp130 cytokine family in the development of bone metastasis. Bone-marrow metastasis is usually the initial step in the formation of bone metastasis, and interaction between tumour cells and bone-marrow cells affects osteoclast formation in bone marrow. Thus IL-6, IL-11 and LIF have been suspected to participate in the formation of osteolytic bone metastasis.159–164 This is the case of A375 melanoma cell line, which formed multiple osteolytic lesions when cells were injected into the left ventricle of mice.165 IL-6 and LIF produced by A375 cell lines may be involved in the differentiation and activation of osteoclasts in association with stromal cells during the development of bone metastasis.166 IL-6 has been reported to be involved in bone destruction in malignant-hypercalcaemia.159–161 Similarly IL-11 produced by endothelial cells and cancer cells may induce the formation of osteolytic bone metastasis.162,163 Akatsu et al. also found that the mouse mammary tumour cell line, MMT060562, released LIF, which in turn stimulated osteoclast formation via a stromal cell-dependent pathway.164 IL-6 has been shown to play a key role in the generation of plasmocytomas151,152, which has been confirmed by Bataille et al.167,168 and more recently by

Nishimoto et al.169 and Zhang et al.170 whereas IL-6, like IL-11, LIF and OSM, induces proliferation in vitro of human plasmocytoma cells via their common signal transducer, gp130. IL-6 is then expressed by myeloma cells and mediates the autocrine growth of myeloma cells.171 Moreover, Garrett et al. have shown that IL-6 produced by activated osteoclasts enhances myeloma growth in vivo.172 The pathogenesis of bone lesions in multiple myeloma involves bone cells and bone-marrow stromal cells,173,174 as well as various molecules such as cytokines or proteinases.175 Raised serum OSM was related to higher serum IL-6, C-reactive protein levels and also 2microglobulin176,177 (which is considered to be the single most important prognostic factor in multiple myeloma).178 Thus, OSM and IL-6 levels may be significant prognosis parameters. In Paget’s disease of bone, the main abnormality concerns osteoclasts, which are increased in size and possess a large number of nuclei.179 IL-6 and IL-6 receptors are strongly expressed by osteoclasts in patients with Paget’s disease and may be involved in the differentiation/activation of osteoclasts during this pathology.180 Rheumatoid arthritis is an autoimmune and systemic inflammatory disease of uncertain aetiology characterized by acute phase proteins in serum, chronic joint inflammation and severe cartilage alterations (until complete destruction). Numerous cytokines have been measured in the serum and/or synovial fluid of

1462 / Heymann and Rousselle

patients with rheumatoid arthritis, which is indicative of their potential in this pathology. These factors include IL-1 and TNF-,181,182 which are able to induce cartilage proteoglycan catabolism in vitro and in vivo,183–185 and the gp130 cytokine family (IL-6, IL-11, OSM, LIF, CT-1, CNTF).186–191 The activity of these cytokines on cartilage metabolism is varied. LIF and OSM promote cartilage degradation in vitro192,193 and in vivo and have induced leukocyte infiltration in goat joints.194,195 All members of the gp130 cytokine family analysed (IL-6, IL-11, OSM, LIF, CNTF) suppressed proteoglycan synthesis in in vitro experiments.193 During rheumatoid arthritis, some potential sources of the gp130 cytokine family are chondrocytes, synoviocytes and leukocytes infiltrating joints (a correlation has been found between LIF expression in synovial fluid and leukocyte count186).191,196–200 The destruction of cartilage in rheumatoid arthritis may be also controlled by the release of proteases and their inhibitors, which degrade various components of the extracellular matrix. Thus, the gp130 cytokine family can influence cartilage degradation by modulating these protease activities.201–205 Despite the numerous studies published on this subject, the role of the gp130 cytokine family in the regulation of cartilage macromolecule metabolism is still uncertain.206 Histologic analysis has revealed peri-articular trabecular bone resorption in patients with rheumatoid arthritis.207 Takayanagi et al. and Fujikawa et al. have described a new mechanism of bone destruction in rheumatoid arthritis in which synovial fibroblasts can support in vitro differentiation of monocytes/macrophages in osteoclasts.208,209 These locally produced factors could contribute at least partially to joint destruction through osteoclastogenesis.210,211

CONCLUDING COMMENTS During the last decade, various soluble factors have been found to act on bone cells. However, it is difficult to establish a hierarchical order for these factors. Members of the gp130 cytokine family appear to play a key role in bone remodelling events by acting on both osteoclasts and osteoblasts. The fact that these factors are detected during osteoarticular pathologies is indicative of their importance. Nevertheless, their exact role (bone apposition, bone resorption) in bone cells remains an open question. Although cytokines, growth factors and hormones are the main protagonists of bone remodelling, phylogeny can provide further clues to this phenomenon.212 Thus, it has been shown that the osteoclast appeared during the evolutionary transition of bony fishes from salt to fresh water where calcium homeostasis could no longer be regulated by transport across epithelia in contact with salt water. Therefore, bone represents a stock of

CYTOKINE, Vol. 12, No. 10 (October, 2000: 1455–1468)

calcium ions that regulate cellular activity, which in turn influences calcium release from bone. Calcium would thus appear to be one of the primary parameters of bone remodelling, acting before cytokines, growth factors and hormones.

REFERENCES 1. Frost HM (1973) Bone remodelling and its relation to metabolic bone diseases. Charles C Thomas Spingfield Ed., Illinois, USA. 2. Teitelbaum SL, Tondravi MM, Ross FP (1997) Osteoclasts, macrophages, and the molecular mechanisms of bone resorption. J Leuk Biol 61:381–388. 3. Athanasou NA (1996) Cellular biology of bone-resorbing cells. J Bone Joint Surg 78A:1096–1112. 4. Blair HC (1998) How the osteoclast degrades bone. Bioessays 20:837–846. 5. Fawcett DW, Raviola E (1994) Bone. In: Fawcett DW, Raviola E. (eds) A textbook of histology, 12th edition. Chapman and Hall, New York, USA, pp 194–233. 6. Jimi E, Nakamura I, Amano H, Taguchi Y, Tsurakai T, Tamura M, Takahashi N, Suda T (1996) Osteoclast function is activated by osteoblastic cells through mechanism involving cell-tocell contact. Endocrinology 137:2187–2190. 7. Ruoslahti E, Boble NA, Kagami S, Border WA (1994) Integrins. Kidney Int 45:s17–s22. 8. Goldring MB, Goldring SR (1990) Skeletal tissue response to cytokines. Clin Orthop Rel Res 258:245–278. 9. Martin TJ, Ng KW (1994) Mechanisms by which cells of the osteoblast lineage control osteoclast formation and activity. J Cell Biochem 56:357–366. 10. Heymann D, Guicheux J, Gouin F, Passuti N, Daculsi G (1998) Cytokines, growth factors and osteoclasts. Cytokine 10: 155–168. 11. Hibi M, Murakami M, Saito M, Hirano T, Taga T, Kishimoto T (1990) Molecular cloning and expression of an IL-6 signal transducer, gp 130. Cell 63:1149–1157. 12. Gearing DP (1993) The leukemia inhibitory factor and its receptor. Adv Immunol 53:31–58. 13. Pennica D, Wood WI, Chien KR (1996) Cardiotrophin-1: a multifunctional cytokine that signals via LIF receptor-gp130 dependent pathways. Cytokine Growth Factor Rev 7:81–91. 14. Sariola H, Sainio K, Arumae U, Sarma M (1994) Neurotrophin and ciliary neurotrophic factor: their biology. Ann Med 26:355–363. 15. Piquet-Pellorce C, Grey L, Mereau A, Heath JK (1994) Are LIF and related cytokines functionally equivalent? Exp Cell Res 213:340–347. 16. Richards CD (1998) Interleukin-6. In: Mire-Sluis AR, Thorpe R (eds) Cytokines. Academic Press, New York, NY, USA, pp 88–108. 17. Leng SX, Elias JA (1997) Interleukin-11. Int J Biochem Cell Biol 28:1059–1062. 18. Yang YC (1993) Interleukin 11: an overview. Stem Cells 11:474–486. 19. Neben S, Turner K (1993) The biology of interleukin 11. Stem Cells 11 (suppl 2):156–162. 20. Yang YC, Yin T (1992) Interleukin-11 and its receptor. Biofactors 4:15–21. 21. Giovanni M, Selleri L, Hermanson GG, Evans GA (1993) Localization of the human oncostatin M gene (OSM) to chromosome 22q12, distal to the Ewing’s sarcoma breakpoint. Cytogenet Cell Genet 62:32–34. 22. Thoma B, Bird TA, Friend DJ, Gearing DP, Dower SK (1994) Oncostatin M and leukemia inhibitory factor trigger overlapping and different signals through partially shared receptor complexes. J Biol Chem 269:6215–6222. 23. Gearing DP, Bruce Ag (1992) Oncostatin M binds the high affinity leukemia inhibitory factor receptor. New Biol 4:61–65. 24. Godard A, Heymann D, Raher S, Anegon I, Peyrat MA, Le Mauff B, Mourray E, Gre´ goire M, Virdee K, Soulillou JP,

gp130 cytokine family and bone cells / 1463 Moreau JF, Jacques Y (1992) High and low affinity receptors for human interleukin for DA cells/leukemia inhibitory factor on human cells. Molecular and cellular distribution. J Biol Chem 267: 3214–3222. 25. Heymann D, Godard A, Raher S, Bentouimou N, Blanchard F, Che´ rel M, Hallet MM, Jacques Y (1996) Leukemia inhibitory factor (LIF) and oncostatin M (OSM) high affinity binding require additional receptor subunits besides GP130 and GP190. Cytokine 8:197–205. 26. Godard A, Gascan H, Naulet J, Peyrat MA, Jacques Y, Soulillou JP, Moreau JF (1988) Biochemical characterization and purification of HILDA, a human lymphokine active on eosinophils and bone marrow cells. Blood 71:1618–1623. 27. Anegon I, Moreau JF, Godard A, Hallet MM, Wong G, Jacques Y, Peyrat MA, Soulillou JP (1990) Production of human interleukin for DA cells (HILDA)/leukemia inhibitory factor (LIF) activated monocytes. Cell Immunol 130:50–65. 28. Derigs HG, Boswell HS (1993) LIF mRNA expression is transcriptionally regulated in murine bone marrow stromal cells. Leukemia 7:630–634. 29. Wetzler M, Talpaz M, Lowe DG, Baiocchi G, Gutterman JU, Kurzrock R (1991) Constitutive expression of leukemia inhibitory factor RNA by human bone marrow stromal cells and modulation by IL-1, TNF- and TGF-. Exp Hematol 19:347– 351. 30. Lu¨ bbert M, Mantovanni L, Lindemann A, Mertelsmann R, Herrmann F (1991) Expression of leukemia inhibitory factor is regulated in human mesenchymal cells. Leukemia 5:361–365. 31. Pollock JH, Blaha MJ, Lavish SA, Stevenson S, Greenfield EM (1996) In vivo demonstration that parathyroid hormone and parathyroid hormone-related protein stimulate expression by osteoblasts of interleukin-6 and leukemia inhibitory factor. J Bone Miner Res 11:754–759. 32. Ishimi Y, Abe E, He Jin C, Miyaura C, Hong MH, Oshida M, Kurosoka H, Yamaguchi Y, Tomida M, Hozumi M, Suda T (1992) Leukemia inhibitory factor/differentiation-stimulating factor (LIF/D-factor): regulation of its production and possible roles in bone metabolism. J Cell Physiol 152:71–78. 33. Marusic A, Kalinowski JF, Jastrzebski S, Lorenzo JA (1993) Production of leukemia inhibitory factor mRNA and protein by malignant and immortalized bone cells. J Bone Miner Res 8:617–624. 34. Greenfield AM, Gornik SA, Horowitz MC, Donahue HJ, Shaw SM (1993) Regulation of cytokine expression in osteoblasts by parathyroid hormone: rapid stimulation of interleukin-6 and leukemia inhibitory factor mRNA. J Bone Miner Res 8:1163–1171. 35. Gascan H, Anegon I, Praloran V, Naulet J, Godard A, Souillou JP, Jacques Y (1990) Constitutive production of human interleukin for DA cells/leukemia inhibitory factor by human tumor cell lines derived from various tissues. J Immunol 14:2592–2598. 36. Malik N, Kallestad JC, Gunderson NL, Austin SC, Neubauer MG, Och V, Marquardt H, Zarling JM, Shobay M, Wei CM, Linsley PS, Rose TM (1989) Molecular cloning, sequence analysis and functional expression of a novel growth regulator: Oncostatin M. Mol Cell Biol 9:2847–2853. 37. Brown TJ, Lioubin MN, Marquardt H (1987) Purification and characterization of cytostatic lymphocytes produced by activated human T-lymphocytes: synergistic antiproliferative activity of transforming growth factor-1, interferon  and oncostatin M for human melanoma cells. J Immunol 139:2977–2983. 38. Grenier A, Dehoux M, Boutten A, Arce-Vicioso M, Durand G, Gougerot-Pocidalo MA, Chollet-Martin S (1999) Oncostatin M production and regulation by human polymorphonuclear neutrophils. Blood 93:1413–1421. 39. Metcalf D, Gearing DP (1989) A myelosclerotic syndrome in mice engrafted with cells producing high levels of leukemia inhibitory factor (LIF). Leukemia 3:847–852. 40. Metcalf D, Gearing DP (1989) Fatal syndrome in mice engrafted with cells producing high levels of leukemia inhibitory factor. Proc Natl Acad Sci USA 86:5948–5952. 41. Allan EH, Hilton DJ, Brown MA, Yumita S, Metcalf D, Gough NM, Ng KW, Nicola NA, Martin TJ (1990) Osteoblasts display receptors for and responses to leukemia-inhibitory factor. J Cell Physiol 145:110–119.

42. Bellido T, Stahl N, Farrugella TJ, Borda V, Yancopoulos GD, Manolagas SC (1996) Detection of receptors for interleukin-6, interleukin-11, leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor in bone marrow stromal/osteoblastic cells. J Clin Invest 97:431–437. 43. Van-Vlasselaer P (1992) Leukemia inhibitory factor (LIF): a growth factor with pleiotropic effects on bone biology. Prog Growth Factor Res 4:337–353. 44. Gouin F, Couillaud S, Cottrel M, Godard A, Passuti N, Heymann D (1999) Presence of leukemia inhibitory factor (LIF) and LIF-receptor chain (gp190) in osteoclast-like cells cultured from human giant cell tumour of bone. Ultrastructural distribution. Cytokine 11:282–289. 45. Soueidan A, Gan OI, Gouin F, Godard A, Heymann D, Jacques Y, Daculsi G (1995) Culturing of cells from giant cell tumour of bone on natural and synthetic calcified substrata: the effect of leukemia inhibitory factor and vitamin D3 on the resorbing activity of osteoclast-like cells. Virchows Arch 426:469–47X. 46. Tamura Y, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y, Koishihara Y, Ohsugi Y, Kumaki K, Taga T, Kishimoto T, Suda T (1993) Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci USA 90:11924–11928. 47. Jay PR, Centrella M, Lorenzo J, Bruce AG, Horowitz MC (1996) Oncostatin-M: a new bone active cytokine that activates osteoblasts and inhibits bone resorption. Endocrinology 137: 1151–1158. 48. Heinrich PC, Behrmann I, Mu¨ ller-Newen G, Shaper F, Graeve L (1998) Interleukin-6-type cytokine signalling through the gp130/Jak pathway. Biochem J 334:297–314. 49. Levy JB, Schindler C, Raz R, Levy DE, Baron R, Horowitz MC (1996) Activation of the JAK-STAT signal transduction pathway by oncostatin-M in cultured human and mouse osteoblastic cells. Endocrinology 137:1159–1165. 50. Bellido T, Borda VZC, Roberson P, Manolagas SC (1997) Activation of the janus kinase/STAT (signal transducer and activator of transcription) signal transduction pathway by interleukin-6-type cytokines promotes osteoblast differentiation. Endocrinology 138: 3666–3676. 51. Lowe C, Gillespie, Pike JW (1995) Leukemia inhibitory factor as a mediator of JAK/STAT activation in murine osteoblasts. J Bone Miner Res 10:1644–1650. 52. Horowitz MC, Levy JB (1995) The LIF/IL-6 subfamily of cytokines induce protein phosphorylation and signal transduction by nonreceptor tyrosine kinases in human and murine osteoblasts. Calcif Tissue Int 56 (suppl 1):S32–S34. 53. Reid IR, Lowe C, Cornish J, Skinner SJM, Hilton DJ, Willson TA, Gearing DP, Martin TJ (1990) Leukemia inhibitory factor: a novel bone-active cytokine. Endocrinology 126: 1416–1420. 54. Rodan SB, Wesolowski G, Hilton DJ, Nicola NA, Rodan GA (1990) Leukemia inhibitory factor binds with high affinity to preosteoblastic RCT-1 cells and potentiates the retinoic acid induction of alkaline phosphatase. Endocrinology 127:1602– 1608. 55. Cornish J, Callon K, King A, Edgar S, Reid IR (1993) The effect of leukemia inhibitory factor on bone in vivo. Endocrinology 132:1359–1366. 56. Jilka RL, Weinstein RS, Bellido T, Parfitt AM, Manolagas SC (1998) Osteoblast programmed cell death (apoptosis): modulation by growth factors and cytokines. J Bone Miner Res 13: 793–802. 57. Noda M, Vogel RL, Hason DM, Rodan GA (1990) Leukemia inhibitory factor suppresses proliferation, alkaline phosphatase activity, and type I collagen messenger ribonucleic acid level and enhances osteopontin mRNA level in murine osteoblast-like (MC3T3-E1) cells. Endocrinology 127:185–190. 58. Lowe C, Cornish J, Martin TJ, Reid IR (1991) Effects of leukemia inhibitory factor on bone resorption and DNA synthesis in neonatal mouse calvaria. Calcif Tissue Int 49:394–397. 59. Lowe C, Cornish J, Callon C, Martin TJ, Reid IR (1991) Regulation of osteoblast proliferation by leukemia inhibitory factor. J Bone Miner Res 6:1277–1283.

1464 / Heymann and Rousselle 60. Cornish J, Callon KE, Edgar SG, Reid IR (1997) Leukemia inhibitory factor is mitogenic to osteoblasts. Bone 21: 243–247. 61. Malaval L, Gupta AK, Aubin JE (1995) Leukemia inhibitory factor inhibits osteogenic differentiation in rat calvaria cell cultures. Endocrinology 136:1411–1418. 62. Malaval L, Gupta AK, Liu F, Delmas PD, Aubin JE (1998) LIF, but not IL-6, regulates osteoprogenitor differentiation in rat calvaria cell cultures: modulation by dexamethasone. J Bone Miner Res 13:175–184. 63. Evans DB, Gerber B, Feyen JH (1994) Recombinant human leukemia inhibitory factor is mitogenic for human bonederived osteoblast-like cells. Biochem Biophys Res Commun 199:220–226. 64. Heymann D, Touchais S, Bohic S, Rohanizadeh S, Coquard C, Passuti N, Daculsi G (1998) Heterotopic implantation of mouse bone-marrow cells. An in vivo model allowing analysis of mineral phases during mineralization processes. Connect Tissue Res 37:219–231. 65. Drize NJ, Gan OI, Chertkov JL, Godard A, Jacques Y (1996) The effect of leukemia inhibitory factor (LIF) on hematopoietic and stromal precursor cells in murine long-term bone marrow culture. Bull Eksp Biol Med 122:325–338. 66. Bohic S, Rohanizadeh R, Touchais S, Godard A, Daculsi G, Heymann D (1998) Leukemia inhibitory factor and oncostatin M influence the mineral phases formed in a murine heterotopic calcification model: a fourier transform-infrared microspectroscopic study. J Bone Miner Res 13:1619–1632. 67. Bohic S, Pilet P, Heymann D (1998) Effects of leukemia inhibitory factor and oncostatin M on bone mineral formed in in vitro rat bone-marrow stromal cell culture: physicochemical aspects. Biochem Biophys Res Commun 253:506–513. 68. Turner RT, Hannon KS, Turner K, Greene VS, Bell NH (1996) Leukemia inhibitory factor produces hypercalcemia in rats without altering bone histomorphometry of the tibia. Calcif Tissue Int 59:301–304. 69. Yamada S, Heymann D, Bouler JM, Daculsi G (1997) Osteoclastic resorption of calcium phosphate ceramics with different hydroxyapatite/-tricalcium phosphate ratios. Biomaterials 18: 1037–1041. 70. van Beek EV, van der Wee-Pals L, van de Ruit M, Nijweide P, Papapoulos S, Lo¨ wik C (1993) Leukemia inhibitory factor inhibits osteoclastic resorption, growth, mineralization, and alkaline phosphatase activity in fetal bone mouse metacarpal bones in culture. J Bone Miner Res 8:191–198. 71. Lorenzo JA, Sousa SL, Leahy CL (1990) Leukemia inhibitory factor (LIF) inhibits basal bone resorption in fetal rat long bone cultures. Cytokine 2:266–271. 72. Abe E, Ishimi Y, Takahashi N, Akatsu T, Ozawa H, Yamana H, Yoshiki S, Suda T (1998) A differentiation-inducing factor produced by the osteoblastic cell line MC3T3-E1 stimulates bone resorption by promoting osteoclast formation. J Bone Miner Res 3:635–645. 73. Heymann D, Gouin F, Guicheux J, Munevar JC, Godard A, Daculsi G (1997) Upmodulation of multinucleated cell formation in long-term human bone marrow cultures by leukemia inhibitory factor (LIF). Cytokine 9:46–52. 74. Heymann D, Guicheux J, Gouin F, Cottrel M, Daculsi G (1998) Oncostatin M stimulates macrophage-polykaryon formation in long-term human bone marrow cultures. Cytokine 10: 98–109. 75. Sarma U, Flanagan AM (1996) Macrophage colonystimulating factor induces substantial osteoclast generation and bone resorption in human bone marrow cultures. Blood 88: 2531–2540. 76. Benahmed M, Heymann D, Berreur M, Cottrel M, Godard A, Daculsi G, Pradal G (1996) Ultrastructural study of degradation of calcium phosphate ceramic by human monocytes and modulation of this activity by HILDA/LIF cytokine. J Histochem Cytochem 44:1131–1140. 77. Sabokbar A, Fujikawa Y, Brett J, Murray DW, Athanasou NA (1996) Increased osteoclastic differentiation by PMMA particle-associated macrophages. Inhibitory effect by

CYTOKINE, Vol. 12, No. 10 (October, 2000: 1455–1468) interleukin 4 and leukemia inhibitory factor. Acta Orthop Scand 67:593–598. 78. Hill PA, Buttle DJ, Jones SJ, Boyde A, Murata M, Reynolds JJ, Meikle MC (1994) Inhibition of bone resorption by selective inactivators of cysteine-proteases. J Cell Biochem 56: 118–130. 79. Hill PA, Murphy G, Docherty AJP, Hembry RM, Millican TA, Reynolds JJ, Meikle MC (1994) The effects of selective inhibitors of matrix metalloproteinases (MMPs) on bone resorption and identification of MMPs and TIMP-1 in isolated osteoclasts. J Cell Sci 107:3055–3064. 80. Varghese S, Yu Kyung, Canalis E (1999) Leukemia inhibitory factor and oncostatin M stimulate collagenase-3 expression in osteoblasts. Am J Physiol 276:E465–E471. 81. Damiens C, Grimaud E, Rousselle AV, Charrier C, Fortun Y, Heymann D, Padrines M (1999) Cysteine protease production by human osteosarcoma cells (MG63, SaOS2) and its modulation by soluble factors. Cytokine (in press). 82. Cowell S, Knauper V, Stewart ML, D’Ortho MP, Stanton H, Hembry RM, Lopez-Otin C, Reynolds JJ, Murphy G (1998) Induction of metalloproteinase activation cascades based on membrane-type 1 matrix metalloproteinase: associated activation of gelatinase A, gelatinase B and collagenase 3. Biochem J 331:453– 458. 83. Shen M, Skoda RC, Cardiff RD, Campos-Torres J, Leder P, Ornitz DM (1994) Expression of LIF in transgenic mice results in altered thymic epithelium and apparent interconversion of thymic node morphologies. Embo J 13:1375–1385. 84. Malik N, Haugen HS, Modrell B, Shoyab M, Clegg CH (1995) Developmental abnormalities in mice transgenic for bovine oncostatin M. Mol Cell Biol 15:2349–2358. 85. Escary JL, Perreau J, Dume´ nil D, Ezine S, Bruˆ let P (1993) Leukaemia inhibitory factor is necessary for maintenance of haematopoietic stem cells and thymocyte stimulation. Nature 363: 361–364. 86. Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Kontgen F, Abbondanzo SJ (1992) Blastocyst implantation depends on maternal expression of leukemia inhibitory factor. Nature 359:76–79. 87. Kawasaki K, Gao YH, Uokose S, Kaji Y, Nakamura T, Suda T, Yoshida K, Taga T, Kishimoto T, Kataoka H, Yuasa T, Norimatsu H, Yamaguchi A (1997) Osteoclasts are present in gp130-deficient mice. Endocrinology 138:4959–4965. 88. Ware CB, Horowitz MC, Renshaw, Hunt JS, Liggitt D, Koblar SA, Gliniak BC, McKenna HJ, Thalia P, Bellina T, Linzhao C, Donovan PJ, Peschon JJ, Barlett PF, Willis CR, Wright BD, Carpenter MK, Davison BL, Gearing DP (1995) Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. Development 121:1283–1299. 89. Taga T (1997) GP 130 and the interleukin-6 family of cytokines. Annu Rev Immunol 15:797–819. 90. Xungxiang D, Williams DA (1997) Interleukin-11: review of molecular, cell biology, and clinical use. Blood 89:3897–3908. 91. Richards CD (1998) Interleukin-6. In: Mire-Sluis AR, Thorpe R (eds) Cytokines. Academic Press, New York, NY, USA, pp 87–100. 92. Barton BE (1996) The biological effects of interleukin 6. Medicinal Res Rev 16:87–109. 93. Bilbe G, Roberts E, Birch M, Evans DB (1996) PCR phenotyping of cytokines, growth factors and their receptors and bone matrix proteins in human osteoblast-like cell lines. Bone 19:437–445. 94. Holt I, Davie MWJ, Marshall MJ (1996) Osteoclasts are not the major source of interleukin-6 in mouse parietal bone. Bone 18:221–226. 95. Frost A, Jonsson KB, Brandstrom H, Ohlsson C, Ljunghall S, Ljunggren O (1998) Interleukin-13 inhibits cell proliferation and stimulates interleukin-6 formation in isolated human osteoblasts. J Clin Endocrinol Metab 83:3285–3289. 96. Kozawa O, Tokuda H, Kaida T, Matsuno H, Uematsu T (1998) Retinoic acid suppresses interleukin-6 synthesis induced by prostaglandins in osteoblasts. Prostaglandins Leukop Essent Fatty Acids 58:215–219.

gp130 cytokine family and bone cells / 1465 97. Siddiqi A, Burrin JM, Wood DF, Monson JP (1998) Tri-iodothyronine regulates the production of interleukin-6 and interleukin-8 in human bone marrow stromal and osteoblast-like cells. J Endocrinol 157:453–461. 98. Kozawa O, Tokuda H, Matsuno H, Uematsu T (1998) Sphingosine modulates interleukin-6 synthesis in osteoblasts. J Cell Biochem 70:338–345. 99. Girasole G, Jilka RL, Passeri G, Boswell S, Boder G, Williams DC, Manolagas SC (1992) 17 beta-estradiol inhibits interleukin-6 production by bone marrow-derived stromal cells and osteoblasts in vitro: a potential mechanism for the antiosteoporotic effect of estrogens. J Clin Invest 89:883–891. 100. Schiller C, Gruber R, Redlich K, Ho GM, Katzgraber F, Willheim M, Pietschmann P, Peterlik M (1997) 17beta-estradiol antagonizes effects of 1alpha, 25-dihydroxyvitamin D3 on interleukin-6 production and osteoclast-like cell formation in mouse bone marrow primary cultures. Endocrinology 138:4567–4571. 101. Littlewood AJ, Russel J, Harvey GR, Hughes DE, Russel RG, Gowen M (1991) The modulation of the expression of IL-6 and its receptor in human osteoblasts in vitro. Endocrinology 129: 1513–1520. 102. Miyaura C, Jin CH, Akatsu T, Abe E, Nakamura Y, Yamaguchi A, Yoshiki S, Matsuda T, Hirano T, Kishimoto T, Suda T (1990) Il-6 produced by osteoblasts and induces bone resorption. J Immunol 145:3297–3303. 103. Hurley MM, Abreu C, Marcello K, Kawaguchi H, Lorenzo J, Kalinowski J, Ray A, Gronowicz G (1996) Regulation of NFIL-6 and IL-6 expression by basic fibroblast growth factor in osteoblasts. J Bone Miner Res 11:760–767. 104. Kumei Y, Shimokawa H, Katano H, Hara E, Akiyama H, Hirano M, Mukai C, Nagaoka S, Whitson PA, Sams CF (1996) Microgravity induces prostaglandin E2 and interleukin-6 production in normal rat osteoblasts: role in bone demineralization. J Biotechnol 47:313–314. 105. Paul SR, Bennet F, Calvetti JA, Kellerher K, Wood CR, O’Hara Jr RM, Leary AC, Sibley B, Clark SC, Williams DA, Yang YC (1990) Molecular cloning of a cDNA encoding interleukin-11, a stromal cell-derived lymphopoietic cytokine. Proc Natl Acad Sci USA 87:7512–7516. 106. Elias JA, Tang W, Horowitz MC (1995) Cytokine and hormonal stimulation of human osteosarcoma interleukin-11 production. Endocrinology 136:489–498. 107. Morinaga Y, Fujita N, Ohishi K, Tsuruo T (1997) Stimulation of interleukin-11 production from osteoblast-like cells by transforming growth factor-beta and tumor cell factors. Int J Cancer 71:422–428. 108. Romas E, Udagawa N, Zhou H, Tamura T, Saito M, Taga T, Hilton DJ, Suda T, Ng KW, Martin TJ (1996) The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures. J Exp Med 183:2581–2591. 109. Kim GS, Kim CH, Choi CS, Park JY, Lee KU (1997) Involvement of different second messengers in parathyroid hormoneand interleukin-1-induced interleukin-6 and interleukin-11 production in human bone marrow stomal cells. J Bone Miner Res 12:896–902. 110. Yang L, Yang YC (1994) Regulation of interleukin (IL)-11 gene expression in IL-1 induced primate bone marrow stromal cells. J Biol Chem 269:32732–32739. 111. Aman MJ, Bug G, Aulitzky WA, Huber C, Peschel C (1996) Inhibition of interleukin-11 by interferon- in human bone marrow stromal cells. Exp Hematol 24:863–867. 112. Gimble JM, Wanker F, Wang CS, Bass H, Wu X, Kelly K, Yancopoulos GD, Hill MR (1994) Regulation of bone marrow stromal cell differentiation by cytokines whose receptors share the gp130 protein. J Cell Biochem 54:122–133. 113. Littlewood AJ, Aarden LA, Evans DB, Russell RG, Gowen M (1991) Human osteoblast-like cells do not respond to interleukin-6. J Bone Miner Res 6:141–148. 114. Kim CH, Cheng SL, Kim GS (1997) Lack of autocrine effects of IL-6 on human bone marrow stromal osteoprogenitor cells. Endocrin Res 23:181–190.

115. Fang MA, Hahn TJ (1991) Effects of interleukin-6 in cellular function in UMR-106-01 osteoblast-like cells. J Bone Miner Res 6:133–139. 116. Bellido T, O’Brien CA, Roberson PK, Manolagas SC (1998) Transcriptional activation of the p21 (WAF1, CIP1, SDI1) gene by interleukin-6 type cytokines. A prerequisite for their prodifferentiating and anti-apoptotic effect on human osteoblastic cells. J Biol Chem 273:21137–21144. 117. Taguchi Y, Yamamoto M, Yamate T, Lin SC, Mocharla H, deTogni P, Nakayama N, Boyce BF, Abe E, Manolagas SC (1998) Interleukin-6-type cytokines stimulates mesenchymal progenitor differentiation toward the osteoblastic lineage. Proc Assoc Am Physicians 110:559–574. 118. Hughes FJ, Howells GL (1993) Interleukin-6 inhibits bone formation in vitro. Bone Miner 21:21–28. 119. Kuhihara N, Bertolini D, Suda T, Akiyama Y, Roodman GD (1990) IL-6 stimulates osteoclast-like multincleated cell formation in long term human marrow cultures by inducing IL-1 release. J Immunol 144:4226–4230. 120. Devlin RD, Reddy SV, Savino R, Ciliberto G, Roodman D (1998) Il-6 mediates the effects of IL-1 or TNF, but not PTHrp or 1,25(OH)2D3, on osteoclast-like cell formation in normal human bone marrow cultures. J Bone Miner Res 13:393–399. 121. Greenfield EM, Shaw SM, Gornik SA, Banks MA (1995) Adenyl cyclase and interleukin 6 are downstream effectors of parathyroid hormone resulting in stimulation of bone resorption. J Clin Invest 96:1238–1244. 122. Grey A, Mitnick MA, Masiukiewicz U, Sun BH, Rudikoff S, Jilka RL, Manolagas SC, Insogna K (1999) A role for interleukin-6 in parathyroid hormone-induced bone resorption in vivo. Endocrinology 140:4683–4690. 123. Holt I, Davie MW, Braidman IP, Marshall MJ (1994) Interleukin-6 does not mediate the stimulation by prostaglandin E2, parathyroid hormone, or 1, 25 dihydroxyvitamin D3 of osteoclast differentiation and bone resorption in neonatal mouse parietal bones. Calcif Tissue Int 55:114–119. 124. de la Mata J, Uy HL, Guise TA, Story B, Boyce BF, Mundy GR, Roodman GD (1995) Interleukin-6 enhances hypercalcemia and bone resorption mediated by parathyroid hormonerelated protein in vivo. J Clin Invest 95:2846–2852. 125. Flanagan AM, Stow MD, Williams R (1995) The effect of interleukin-6 and soluble interleukin-6 receptor protein on the bone resorptive activity of human osteoclasts generated in vitro. J Pathol 176:289–297. 126. Shinar DM, Sato M, Rodan GA (1990) The effect of hemopoietic growth factors on the generation of osteoclast-like cells in mouse bone marrow cultures. Endocrinology 126:1728–1735. 127. Taichman RS, Reilly MJ, Verma RS, Emerson SG (1997) Augmented production of interleukin-6 by normal human osteoblasts in response to CD34 + hematopoietic bone marrow cells in vitro. Blood 89:1165–1172. 128. Pierelli L, Scambia G, d’Onofrio G, Ciarli M, Fattorossi A, Bonanno G, Menichella G, Battaglia A, Benedetti-Panici P, Tommasi M, Mancuso S, Leone G (1997) Generation of multinuclear tartrate-resistant acid phosphatase positive osteoclasts in liquid culture of purified human peripheral blood CD34+ progenitors. Br J Haematology 96:64–69. 129. Sandhu JS, Gorczynki RM, Waddell J, Nguyen H, Squires J, Waddell J, Boynton EL, Hozumi M (1999) Effects of interleukin-6 secreted by engineered human stromal cells on osteoclasts in human bone. Bone 24:217–227. 130. Reddy SV, Takahashi S, Dallas M, Williams RE, Neckers L, Roodman GD (1994) Interleukin-6 antisense deoxyoligonucleotides inhibit bone resorption by giant cells from human giant cell tumors of bone. J Bone Miner Res 9:753–757. 131. Giovanni M, Strip P, Serra M, Sironi M, Fincato G, Colotta F, Bonafe M, Biunno I, Mantovanni A, Orlandini AZ, Brandi ML, Pastano R, Bagnara GP (1996) Production of interleukin-6 by human osteoclast-like cells from giant cell tumor of bone. Int J Oncol 8:297–303. 132. Udagawa N, Takahashi N, Katagiri T, Tamura T, Waida S, Findlay DM, Martin TJ, Hirota H, Taga T, Kishimoto T, Suda T (1995) Interleukin (IL)-6 induction of osteoclast differentiation

1466 / Heymann and Rousselle depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors. J Exp Med 182:1461–1468. 133. Gao Y, Morita I, Maruo N, Kubota T, Murota S, Aso T (1998) Expression of IL-6 receptor and GP130 in mouse bone marrow cells during osteoclast differentiation. Bone 22:487–493. 134. Adebanjo OA, Moonga BS, Yamate T, Sun L, Minkin C, Abe E, Zaidi M (1998) Mode of action of interleukin-6 on mature osteoclasts. Novel interaction with extracellular Ca2+ sensing in the regulation of osteoclastic bone resorption. J Cell Biol 142: 1347–1356. 135. Jilka RL, Hangoc G, Girasole G, Passeri G, Williams DC, Abrams JS, Boyce B, Broxmeyer H, Manolagas SC (1992) Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 257:88–91. 136. Poli V, Balena R, Fattori E, Markatos A, Yamamoto M, Tanaka H, Ciliberto G, Rodan GA, Costantini F (1994) Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. Embo J 13:1189–1196. 137. McKane WR, Khosla S, Peterson JM, Egan K, Riggs BL (1994) Circulating levels of cytokines that modulate bone resorption: effects of age and menopause in women. J Bone Miner Res 9: 1313–1318. 138. Bismar H, Diel I, Ziegler R, Pfeilschifter J (1995) Increased cytokine secretion by human bone marrow cells after menopause or discontinuation of estrogen replacement. J Clin Endocrinol Metab 80:3351–3355. 139. Binkley NC, Sun WH, Checovich MM, Roecker EB, Kimmel DB, Ersler WB (1994) Effects of recombinant human interleukin-6 administration on bone in rhesus monkeys. Lymphokine Cytokine Res 13:221–226. 140. Kimble RB, Bain S, Pacifici R (1997) The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice. J Bone Miner Res 12:935–941. 141. Sunyer T, Lewis J, Collins-Osdoby P, Osdoby P (1999) Estrogen’s bone protective effects may involve differential IL-1 receptor regulation in human osteoclast-like cells. J Clin Invest 103:1409–1418. 142. Bellido T, Jilka RL, Boyce BF, Girasole G, Broxmeyer H, Dalrymphe SA, Murray R, Manolagas SC (1995) Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. The role of the androgen receptors. J Clin Invest 95:2886–2895. 143. Lin SC, Yamate T, Taguchi Y, Borda VZC, Girasole G, O’Brien CA, Bellido T, Abe T, Manolagas SC (1997) Regulation of the gp80 and gp130 subunits of the IL-6 receptor by sex steroids in the murine bone marrow. J Clin Invest 100:1980–1990. 144. Nishida S, Okimoto N, Okazaki Y, Yamaguchi A, Kumegawa M, Yasukawa K, Murayama K, Nakamura T (1998) Effect of monoclonal anti-human gp130 antibody (GPX7) on bone turnover in normal and ovariectomized rats. Calcif Tissue Int 62:227–236. 145. Girasole G, Passeri G, Jilka RL, Manolagas C (1994) Interleukin-11: a new cytokine critical for osteoclast development. J Clin Invest 93:1516–1524. 146. Hill PA, Tumber A, Papaioannou S, Meikle MC (1998) The cellular actions of interleukin-11 on bone resorption in vitro. Endocrinology 139:1564–1572. 147. Morinaga Y, Fujita N, Ohishi K, Zhang Y, Tsuruo T (1998) Suppression of interleukin-11-mediated bone resorption by cyclooxygenases inhibitors. J Cell Physiol 175:247–254. 148. Verhaeghe J, van Haerck E, van Bree R, Bouillon R, Dequeker J, Keith JC (1998) Recombinant human interleukin-11 does not modify biochemical parameters of bone remodeling and bone mineral density in adult ovariectomized rats. J Interfer Cytok Res 18:49–53. 149. Kusano K, Miyaura C, Inada M, Tamura T, Ito A, Nagase H, Kamoi K, Suda T (1998) Regulation of matrixmetalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption. Endocrinology 139:1338–1345. 150. Kitamura H, Hawata H, Takahashi F, Higuchi Y, Furuichi T, Ohkawa H (1995) Bone marrow neutrophilia and suppressed bone turnover in human interleukin-6 transgenic mice. A cellular relationship among hematopoietic cells, osteoblasts, and

CYTOKINE, Vol. 12, No. 10 (October, 2000: 1455–1468) osteoclasts mediated by stromal cells in bone marrow. Am J Pathol 147:1682–1692. 151. Suematsu S, Matsuda T, Aozasa K, Akira S, Nakano N, Ohno S, Miyazaki J, Yamamura K, Hirano T, Kishimoto T (1989) IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci USA 86:7547–7551. 152. Suematsu S, Matsusaka T, Matsuda T, Ohno S, Miyazaki J, Yamamura K, Hirano T, Kishimoto T (1992) Generation of plasmacytomas with the chromosomal translocation (12; 15) in interleukin 6 transgenic mice. Proc Natl Acad Sci USA 89:232–235. 153. Tang W, Geba GP, Zheng T, Ray P, Hona RJ, Kuhn C 3rd, Flavell RA, Elias JA (1996) Targeted expression of IL-11 in the murine airway causes lymphocytic inflammation, branchial remodelling, and airways obstruction. J Clin Invest 98:2845–2853. 154. Nandurkan HH, Robb L, Tarlinton D, Barnett L, Kontgen F, Begley CG (1997) Adult mice with targeted mutation of the interleukin-11 receptor (IL11Ra) display normal hematopoiesis. Blood 90:2148–2159. 155. Gouin F, Heymann D, Raher S, De Groote D, Passuti N, Daculsi G, Godard A (1998) Increased levels of leukemia inhibitory factor (LIF) in urine and tissue culture supernatant from human primary bone tumours. Cytokine 10:110–114. 156. Gouin F, Moreau A, Couillaud S, Guicheux J, Passuti N, Godard A, Heymann D (1999) Expression of leukemia inhibitory factor by cartilage-forming tumors of bone: an immunohistochemical study. J Orthop Res 17:301–305. 157. Mills BG, Frausto A (1997) Cytokines expressed in multinucleated cells: Paget’s disease and giant cell tumors versus normal bone. Calcified Tissue Int 61:16–21. 158. Hiraga T, Tanaka S, Ikegame M, Koizumi M, Iguchi H, Nakajima T, Ozawa H (1998) Morphology of bone metastasis. Eur J Cancer 34:230–239. 159. Yoneda T (1993) Cytokines in bone: local translators in cell-to-cell communications. In: Noda M (ed.) Cellular and Molecular Biology of Bone. Academic Press, New York, NY, USA, pp 375–412. 160. Roodmann GD, Kuhihara N, Ohsaki Y, Kukita A, Hosking D, Demulder A, Smith JF, Singer FR (1992) Interleukin 6: a potential autocrine/paracrine factor in Paget’s disease of bone. J Clin Invest 89:46–52. 161. Ishimi Y, Miyaura C, Jin CH, Akatsu T, Abe E, Nakamura Y, Ymaguchi A, Yoshiki S, Matsuda T, Hirano T, Kishimoto T, Suda T (1990) IL-6 is produced by osteoblasts and induces bone resorption. J Immunol 145:3297–3303. 162. Zhang Y, Fugita N, Oh-hara T, Morinaga Y, Yamada M, Tsuruo T (1998) Production of interleukin-11 in bone-derived endothelial cells and its role in the formation of osteolytic bone metastasis. Oncogene 16:693–703. 163. Lacroix M, Siwek B, Marie PJ, Body JJ (1998) Production and regulation of interleukin-11 by breast cancer cells. Cancer Lett 127:29–35. 164. Akatsu T, Ono K, Katayama Y, Tamura T, Nishikawa M, Kugai N, Yamamoto M, Nagata N (1998) The mouse mammary tumor cell line, MMT060562, produces prostaglandin E2 and leukemia inhibitory factor and supports osteoclast formation in vitro via a stromal dependent pathway. J Bone Miner Res 13: 400–408. 165. Hiraga T, Nakajima T, Ozawa H (1995) Bone resorption induced by a metastatic human melanoma cell line. Bone 16: 349–356. 166. Heymann D, Blanchard F, Raher S, De Groote D, Godard A (1995) Modulation of LIF expression in human melanoma cells by oncostatin M. Immunol Lett 46:2445–2451. 167. Bataille R, Chappard D, Klein B (1992) The critical role of interleukin-6, interleukin-1 and macrophage colony-stimulating factor in the pathogenesis of bone lesions in multiple myeloma. Int J Clin Lab Res 21:283–287. 168. Bataille R, Chappard D, Klein B (1992) Mechanisms of bone lesions in multiple myeloma. Hematol Oncol Clin North Am 6:285–295. 169. Nishimoto N, Ogata A, Shima Y, Ogawa H, Nakagawa M, Sugiyama H, Yoshizaki K, Kishimoto T (1994) Oncostatin M, leukemia inhibitory factor, and interleukin 6 induce the proliferation

gp130 cytokine family and bone cells / 1467 of human plasmacytoma cells via the common signal transducer, gp 130. J Exp Med 179:1343–1347. 170. Zhang XG, Gu JJ, Lu ZY, Yasukawa K, Yancopoulos GD, Turner K, Shoyab M, Taga T, Kishimoto T, Bataille R, Klein B (1994) Ciliary neurotrophic factor, interleukin 11, leukemia inhibitory factor, and oncostatin M are growth factors for human myeloma cell lines using the interleukin 6 signal transducer GP130. J Exp Med 177:1337–1342. 171. Kishimoto T, Akira S, Narazaki M, Taga T (1995) Interleukin-family of cytokine and gp130. Blood 86:1243–1254. 172. Garrett IR, Dallas S, Bonewald LF, Radi J, Mundy GR (1995) Evidence that interleukin 6 produced by osteoclasts enhances myeloma cell growth in vivo. Bone 16:184. 173. Roodman GD (1997) Mechanisms of bone lesions in multiple myeloma and lymphoma. Cancer 80:1557–1563. 174. Caligaris-Cappio F, Bergui L, Grgoretti MG, Gaidano G, Gaboli G, Schena M, Zallone AZ, Marchisio PC (1991) Role of bone marrow stromal cells in the growth of human multiple myeloma. Blood 77:2688–2693. 175. Barille S, Akhoundi C, Colette M, Mellerin MP, Rapp MJ, Harousseau JL, Bataille R, Amiot M (1997) Metalloproteinases in multiple myeloma: production of matrix metalloproteinase-9 (MMP-9), activation of proMMP-2, and induction of MMP-1 by myeloma cells. Blood 90:1649–1655. 176. Pielliniemi TT, Irjala K, Mattila K, Pulkki K, Rajama¨ ki A, Tienhaara A, Laako M, Lahtinen R (1995) Immunoreactive interleukin-6 and acute phase proteins as prognostic factors in multiple myeloma. Blood 85:765–771. 177. Koskela K, Pielliniemi TT, Remes K, Rajama¨ ki A, Pulkki K (1997) Serum oncostatin M in multiple myeloma: association with prognostic factors. British J Haematol 96:158–160. 178. Bataille R, Boccadoro M, Klein B, Durie B, Pileri A (1992) C-reactive protein and 2microglobulin produce a simple and powerful myeloma staging system. Blood 80:733–737. 179. Meunier PJ, Coindre JM, Edouard CM, Arlot ME (1980) Bone histomorphometry in Paget’s disease. Arthritis Rheum 23: 1095–1103. 180. Hoyland JA, Freemont AJ, Sharpe PT (1994) Interleukin-6, IL-6 receptor and Il-6 nuclear factor gene expression in Paget’s disease. J Bone Miner Res 9:75–80. 181. Ahtomonte L, Zoli A, Mirone P, Scolieri P, Magro M (1992) Serum levels of interleukin-1 beta, tumor necrosis factor alpha and inteleukin-2 in rheumatoid arthritis. Correlation with disease activity. Clin Rheumatol 11:202–205. 182. Tetta C, Giovanni C, Modena V, di Vittorio C, Baglioni C (1990) Tumor necrosis factor in serum and synovial fluid of patients with active and severe rheumatoid arthritis. Ann Rheum Dis 49: 665–667. 183. Saklatvala J (1986) Tumour necrosis factor stimulates resorption and inhibit synthesis of proteoglycan in cartilage. Nature 322:547–549. 184. Pettipher ER, Higgs GA, Henderson B (1986) Interleukin-1 induces leukocyte infiltration and cartilage proteoglycan degradation in the synovial joint. Proc Natl Acad Sci USA 83:8749–8753. 185. Henderson B, Pettipher ER (1989) Arthritogenic actions of recombinant IL-1 and tumour necrosis factor alpha in the rabbit: evidence for synergistic interactions between cytokines in vivo. Clin Exp Immunol 75:306–310. 186. Waring PM, Carroll GJ, Kandiah DA, Burski G, Metcalf D (1993) Increased levels of leukemia inhibitory factor in synovial fluid from patients with rheumatoid arthritis and other inflammatory athritides. Arthritis Rheum 36:911–915. 187. Hui W, Bell M, Carroll G (1997) Detection of oncostatin M in synovial fluid from patients with rheumatoid arthritis. Ann Rheum Dis 56:184–187. 188. Houssiau FA, DeVogelaer JP, Van Damme J, de Deuxchaines CN, Van Snick J (1988) Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritis. Arthritis Rheum 31:784–788. 189. Wood NC, Symons JA, Dickens E, Duff GW (1992) In situ hybridization of IL-6 in rheumatoid arthritis. Clin Exp Immunol 87:183–189.

190. Okamoto H, Yamamura M, Morita Y, Harada S, Makino H, Ota Z (1997) The synovial expression and serum levels of interleukin-6, interlukin-11, leukemia inhibitory factor, and oncostatin M in rheumatoid arthritis. Arthritis Rheum 40:1096–1105. 191. Carroll G, Bell M, Wang H, Chapman H, Mills J (1998) Antagonism of the IL-6 cytokine subfamily—a potential strategy for more effective therapy in rheumatoid arthritis. Inflamm Res 47:1–7. 192. Carroll GJ, Bell MC (1993) Leukemia inhibitory factor stimulates proteoglycan resorption in porcine articular cartilage. Rheumatol Int 13:5–8. 193. Wang H, Bell MC, Carroll GJ (1996) Oncostatin M stimulates resorption and inhibits synthesis of proteoglycan in pig cartilage explants. Cytokine 8:495–500. 194. Carroll GJ, Bell MC, Chapman HM, Mills JN, Robinson WF (1995) Leukemia inhibitory factor induces leukocyte infiltration and cartilage proteoglycan degradation in goat joints. J Interferon Cytokine Res 15:567–573. 195. Bell MC, Carroll GJ, Chapman HM, Mills JN, Hui W (1999) Oncostatin M induces leukocytes infiltration and cartilage proteoglycan degradation in vivo in goat joints. Arthritis Rheum 42:2543–2551. 196. Lotz M, Moats T, Villiger PM (1992) Leukemia inhibitory factor is expressed in cartilage and synovium and can contribute to the pathogenesis of arthritis. J Clin Invest 90:888–896. 197. Villiger PM, Geng Y, Lotz M (1993) Induction of cytokine expression by leukemia inhibitory factor. J Clin Invest 91:1575–1581. 198. Dechanet J, Taupin JL, Chomarat P, Rissoan MC, Moreau JF, Banchereau J, Miossec P (1994) Interleukin-4 but not interleukin-10 inhibits the production of leukemia inhibitory factor by rheumatoid synovium and synoviocytes. Eur J Immunol 24: 3222–3228. 199. Henrotin YE, De Groote D, Labasse AH, Gaspar SE, Zheng SX, Geenen VG, Reginster JYL (1996) Effects of exogenous IL-1, TNF-, IL-6, IL-8 and LIF on cytokine production by human chondrocytes. Osteoarthritis Cartilage 4:163–173. 200. Hermann JA, Hall MA, Maini RN, Feldmann M, Brennan FM (1998) Important immunoregulatory role of interleukin-11 in the inflammatory process in rheumatoid arthritis. Arthritis Rheum 41:1388–1397. 201. Hamilton JA, Leizer T, Piccoli DS, Royston KM, Butler DM, Croatto M (1991) Oncostatin M stimulates urokinase-type plasminogen activator activity in human synovial fibroblasts. Biochem Biophys Res Commun 180:652–659. 202. Maier R, Ganu V, Lotz M (1993) Interleukin-11, an inducible cytokine in human articular chondrocytes and synoviocytes, stimulates the production of the tissue inhibitor of metalloproteinases. J Biol Chem 268:21527–21532. 203. Nemoto O, Yamada H, Mukaidai M, Shimmei M (1996) Stimulation of TIMP-1 production by oncostatin M in human articular cartilage. Arthritis Rheum 39:560–566. 204. Langdon C, Leith J, Smith F, Richards CD (1997) Oncostatin-M stimulates monocyte chemoattractant protein-1- and interleukin-1-induced matrix metallopproteinase-1 production by human synovial fibroblasts in vitro. Arthritis Rheum 40:2139–2146. 205. Li WQ, Zafarullah M (1998) Oncostatin M up-regulates tissue inhibitor of metalloproteinases-3 gene expression in articular chondrocytes via de novo transcription, protein synthesis, and tyrosine kinase- and mitogen-activated protein kinase-dependent mechanisms. J Immunol 161:5000–5007. 206. Carroll G, Bell M (1997) Role of oncostatin M in the regulation of cartilage macromolecule metabolism: comment on the article by Nemoto et al. Arthritis Rheum 40:589–590. 207. Shimizu S, Shizawa K, Imura S, Fujita T (1985) Quantitative histologic studies on the pathogenesis of periarticular osteoporosis in rheumatoid arthritis. Arthritis Rheum 28:25–31. 208. Takayanagi H, Oda H, Yamamoto S, Kawaguchi H, Tanaka S, Nishikawa T, Koshihara Y (1997) A new mechanism of bone destruction in rheumatoid arthritis: synovial fibroblasts induce osteoclastogenesis. Biochem Biophys Res Commun 240:279–286. 209. Fujikawa Y, Sabokbar A, Athanasou NA (1996) Human osteoclast formation and bone resorption by monocytes and synovial macrophages in rheumatoid arthritis. Ann Rheum Dis 55:816–822. 210. Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I, Yamaguchi A, Kishimoto T, Suda T, Kashiwazaki S

1468 / Heymann and Rousselle (1996) Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 11:88–95. 211. Lisignaly G, Piacentini A, Toneguzzi S, Grassi F, Cocchini B, Fenuzzi A, Geraltieri G, Facchini A (2000) Osteoblasts and stromal cells isolated from femora in rheumatoid arthritis (RA) and

CYTOKINE, Vol. 12, No. 10 (October, 2000: 1455–1468) osteoarthritis (OA) patients express IL-11, leukemia inhibitory factor and oncostatin M Clin Exp Immunol 119:346–353. 212. Blair HC, Sclesinger PH, Ross FP, Teitelbaum SL (1993) Recent advances toward understanding osteoclast physiology. Clin Orthop Rel Res 294:7–22.