Prostaglandins and Proinflammatory Cytokines

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Chapter 7

Prostaglandins and Proinflammatory Cytokines Lawrence G. Raisz, M.D. Joseph A. Lorenzo, M.D.

Interim Director, Musculoskeletal Institute, Board of Trustees Distinguished Professor of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, MC-3805, Farmington, CT 06030 Director, Bone Biology Research, Professor of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, MC 1317, Farmington, CT 06030–1317.

IV. The Role that Proinflammatory Cytokines have in Bone and Cartilage Metabolism References

I. Introduction II. Prostaglandins III. The Role that Cytokines have in Osteoclast Formation and Function

I. INTRODUCTION

in skeletal tissues. The source of prostaglandins, arachidonate, may be itself a mediator, as well as leukotrienes, which are products of lipoxygenase [2, 3]. Prostaglandins are multifunctional regulators in that they have both stimulatory and inhibitory effects on bone formation and bone resorption as well as biphasic effects on cartilage. Largely because bone has been studied more extensively, a reasonable description of the pattern of physiologic and pathologic responses can now be provided, although there are still many gaps. The role of prostaglandins in cartilage has been less completely studied. Interpretation is further confounded by the fact that many different cell types, species, and in vitro and in vivo conditions have been examined. Identification of specific receptors for prostaglandins, particularly prostaglandin E2 (PGE2), which is the most abundant product in bone cells, has provided a substantial amount of new information. Both transgenic mouse models in which specific receptors

This chapter has been extensively revised since the previous edition to accommodate the remarkable amount of new information that has been developed during the last 5 years in studies of prostaglandins and cytokines in bone and cartilage. Only key references from the previous edition have been retained and the reader is referred to that edition for background information on earlier studies.

II. PROSTAGLANDINS Prostaglandins are critical local regulators of skeletal metabolism that have been shown to play key roles in both physiologic regulation and pathologic responses [1]. In addition to prostaglandins, which are produced by cyclooxygenase, other lipid mediators can be produced Dynamics of Bone and Cartilage Metabolism

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have been deleted and selective receptor agonists and antagonists are now available for study.

A. Regulation of Prostaglandin Synthesis Many types of cells in the skeleton can produce prostaglandins and this production is highly regulated. Prostaglandin production in osteoblastic cells can be stimulated by cytokines, growth factors, nitric oxide, and mechanical forces. Prostaglandins themselves increase their own production (auto-regulation) [4]. This has also been shown for prostaglandin production in chondrocytes. In addition hematopoietic cells, particularly cells of the monocyte/macrophage lineage, and synovial cells can play a prominent role in prostaglandin production in inflammatory disorders. Regulation of prostaglandin production is largely through changes in the inducible form of cyclooxygenase (COX-2). However, the constitutive cyclooxygenase (COX-1) may play a role, particularly in rapid initial responses in which release of arachidonate by phospholipase leads to immediate production of prostaglandins. This may occur in response to both mechanical forces and inflammation [5]. However, the full response of skeletal tissue to mechanical force and inflammation as well as in fracture repair requires COX-2 [6–11]. Recent studies have suggested that the response of the skeleton to changes in ion concentration might also be prostaglandin dependent. High calcium concentrations can induce COX-2 [12]. The stimulation of bone resorption in organ culture that occurs in acid culture medium appears to be prostaglandin dependent [13, 14]. The physiologic importance of this is unknown. However, prostaglandins can inhibit osteoclast function [15]. Thus, if the high concentrations of calcium and hydrogen ions that are produced during osteoclastic bone resorption can induce COX-2, this might provide a mechanism for stopping their activity and, hence, limiting the depth of resorption cavities. Studies using mice in which the COX-2 gene has been deleted clearly demonstrate a critical role for this enzyme in the stimulation of bone resorption by a number of agonists [10] in fracture healing [6, 9], in the osteolysis in response to implants [8], and probably also in heterotopic ossification, based on clinical data [16], as well as on the diminished response to BMP-2 implants in COX-2 knockout animals [11]. The major product of COX-2 in bone cells and probably also in cartilage cells appears to be PGE2 and, hence, membrane-associated PGE2 synthase is also critical for bone resorption and other responses [17]. Studies on the induction of COX-2 have suggested that both the protein kinase-A (PKA) and protein kinase-C (PKC) pathways are involved. However, studies using

selective prostaglandin receptor agonists have supported a greater role for cAMP and PKA activation, particularly through the prostaglandin EP2 receptor [18]. The regulation of COX-2 in cartilage has been less well studied, but chondrocytes appear to show similar responses to those of osteoblasts. Cytokines such as IL-1, growth factors, and mechanical forces can all induce COX-2 in chondrocytes [19–22]. The role of COX-2 in the response of the skeleton to mechanical forces has received increasing attention [23]. A cellular model for mechanical force, the application of fluid shear stress to osteoblast or osteocyte cell cultures, has confirmed the critical role of COX-2 [7, 24]. The anabolic response to mechanical loading can be blocked by selective COX-2 inhibitors [25, 26]. The effects of fluid shear appear to be mediated through cAMP and an ERK signaling pathway [12, 27] and to increased function of gap junctions [28–30]. Signal transduction can occur through cAMP, but likely also through other pathways.

B. Prostaglandins and Bone Resorption Studies using receptor knockout animals, selective agonists, and specialized cell culture models have helped to identify the multiple mechanisms and target cells of prostaglandin bone resorption. Probably the most important effect is the ability of PGE2 to stimulate RANKL production in cells of the osteoblast lineage and perhaps other marrow cells [31]. This effect can be diminished by knocking out either the EP2 or the EP4 receptor, but the latter appears to have a somewhat greater role [32–36]. In fetal rat organ cultures EP4 agonists stimulate resorption, while EP2 agonists are ineffective [37]. In addition to stimulating RANKL, PGE2 may inhibit the production of the decoy receptor osteoprotegerin (OPG), although this has not been found in all of the models tested [38–40]. While the EP2 receptor plays a role in the response of osteoblasts to PGE2, it also has a role in cells of the hematopoietic lineage that give rise to osteoclast [36]. Addition of PGE2 can increase osteoclast production by spleen cells treated with maximally effective concentrations of macrophage colony stimulating factor (M-CSF) and RANKL [41, 42]. Knockout of EP2 receptors in spleen cells reduces the number of osteoclast produced in response to PGE2 [36, 42]. In vivo studies have shown that the response to lipopolysaccharide is decreased in EP4 knockout mice, while the hypercalcemic effect of PGE2 is reduced in EP2 receptor knockout mice [40, 43]. In addition to their predominant effect to stimulate the formation, differentiation, and extend the lifespan

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of osteoclast, prostaglandins have a direct inhibitory effect on osteoclast function. This effect may be mediated by the EP4 receptor [15].

chondrocytes, largely through induction of COX-2 [21, 65, 67, 68]. In addition to a critical role for COX-2, the microsomal PGE synthase is required for these responses [69]. The role of specific prostaglandin receptors has been studied in collagen antibody-induced arthritis in mice. Animals lacking the EP4 receptor show reduced bone destruction and cartilage collagen breakdown in this model [70]. Prostaglandins have complex effects on chondrocyte replication, differentiation and cell death [71]. In an experimental model of osteoarthritis dual inhibition of 5 lipoxygenase and cyclooxygenase resulted in decreased cell death [72]. In cultured chondrocytes from humans with osteoarthritis, nitric oxide induction of cell death is enhanced by induction of COX-2 and production of PGE2. On the other hand PGE2 has been shown to stimulate production and degradation of proteoglycan and increase collagen synthesis in rat chondrocyte cultures [73, 74]. These effects may be mediated by activation of the EP2 and EP4 receptors [75].

C. Prostaglandins and Bone Formation Exogenous PGE can stimulate both endosteal and periosteal bone formation, that is, both modeling and remodeling of the skeleton. This effect persists even in old experimental animals [44, 45]. The role of cell replication in this response is not entirely clear. Under different conditions PGE2 can inhibit or stimulate osteoblastic cell replication [46, 47]. On the other hand, differentiation and colony formation in osteoblastic cell cultures is consistently enhanced by PGE2 [48–50]. Here again, there is a biphasic effect of PGE2, in that collagen synthesis is inhibited in differentiated osteoblasts and in some osteoblastic cell lines [51]. The anabolic effects of PGE2 may be mediated by both EP2 and EP4 receptors. Agonists for both receptors can increase collagen synthesis in fetal rat calvarial organ cultures [37]. A selective EP2 agonist was found to stimulate local bone formation and enhance fracture healing [52, 53]. Inhibitors of the EP4 receptor can impair the anabolic response to PGE2 [54, 55] and selective agonists can increase bone formation and prevent bone loss [56]. There are also data indicating that prostaglandins of the F series can be anabolic in bone [57]. The mechanism of the anabolic effect of PGE2 is not fully understood. The enhancement of osteoblast differentiation appears to be at least in part cAMP dependent, and it probably involves stimulation of the production of endogenous growth factors [49]. Prior studies suggested that increased activity of IGF-1 or VEGF might mediate the anabolic effect [58, 59]. Stimulation of production or enhancement of the response to BMP-2 and BMP-7 have been implicated [60, 61]. Prostaglandins, particularly PGF2α, can also stimulate FGF production, thus leading to a new amplification loop, since FGF in turn can stimulate COX-2 [62, 63]. A dual pathway is likely, for example PGE2 stimulates bone sialoprotein (BSP) expression both through cAMP and FGF2 response elements in the BSP promoter [64].

E. Clinical Implications While there is some evidence that prostaglandins may play important roles in diseases of bone and cartilage, their relative importance compared to other regulators and the precise pathways by which they act are not understood [76–78]. For example, the impaired fracture healing in COX-2-deficient or NSAID-treated animals and humans could be due to effects on platelets, vessels, inflammatory mediators, or fibroblastic cells in the initial phase, as well as to effects on cartilage and bone in subsequent steps. The same may apply for their role in heterotopic ossification, prosthetic loosening and the bone loss associated with immobilization and inflammation. There is direct evidence for an anabolic effect of prostaglandins in infants given infusions of PGE1 and more recently a similar response has been observed in an older patient who developed hypertrophic osteoarthropathy after PGE1 infusion for congestive heart failure [79]. Impact loading can increase PGE2 production in human bone [80]. A role in the pathogenesis of osteoporosis has been suggested based on epidemiologic studies of anti-NSAIDs, as well as some animal studies, but the data are contradictory [81–83].

D. Prostaglandins and Cartilage The fact that NSAIDs can not only inhibit inflammatory responses but may also reduce cartilage degradation in humans and in animal models of arthritis has led to extensive study of the role of prostaglandins in cartilage and adjacent synovial tissue [65, 66]. Cytokines and nitric oxide can increase prostaglandin production in

III. THE ROLE THAT CYTOKINES HAVE IN OSTEOCLAST FORMATION AND FUNCTION Osteoclast are multinuclear giant cells with the unique ability to efficiently resorb both the mineral and organic

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118 components of bone [84]. They form from mononuclear cells, which derive from myeloid lineage hematopoietic precursors. The role that cytokines play in the regulation of osteoclast has been made clearer in recent years by the discovery of a tumor necrosis factor superfamily member and its receptors that are critical for osteoclast formation, activity, and survival [85, 86]. This cytokine was named receptor activator of nuclear factor κB ligand (RANKL, TNFSF11) [87]. It was originally identified as a product of activated T-lymphocytes [87, 88] and it exists either as a membrane-bound or a soluble product whose form is determined by both alternate gene transcription and cleavage of the membranebound form by proteases [89]. Stimulators of resorption enhance production of RANKL, which binds to its receptor RANK (TNFRSF11A) on osteoclast precursor cells [86]. This interaction initiates a series of second messenger steps that mediate osteoclast formation from mononuclear precursors, resorptive activity, and osteoclast survival. In addition, a variety of cells in bone produce a soluble decoy receptor, osteoprotegerin (OPG, TNFRSF11B) [90], which binds RANKL and prevents its interaction with RANK. Thus, OPG is a negative regulator of osteoclastic resorption. Some hormonal stimulators of bone resorption, such as parathyroid hormone [91] and 1,25 (OH)2 vitamin D [92], increase the production of RANKL and inhibit the production of OPG in stromal and osteoblastic cells. This reciprocal regulation of RANKL and OPG likely enhances the resorptive activity of these agents. Other cytokines such as interleukin-1 and tumor necrosis factor [93] stimulate RANKL but have either no effect or are stimulators of OPG production [94]. The second cytokine that is critical for osteoclast differentiation is macrophage colony-stimulating factor (M-CSF or CSF-1) [95]. M-CSF was originally identified as a regulator of macrophage differentiation. However, it was subsequently found that the defect in the op/op mouse, which presents with defective osteoclast formation and osteopetrosis, is caused by a mutation in the M-CSF gene [96, 97]. This point mutation introduces a stop codon in the sequence, which prevents expression of the protein. Subsequent studies have shown that M-CSF is a mitogen for early myeloid precursor cells, which regulates the lineage commitment of myeloid precursor cells towards osteoclast [95]. Exposure of myeloid precursors to M-CSF also induces RANK expression [98]. Like RANKL, M-CSF enhances the survival of mature osteoclast [99]. However, in contrast to the actions of RANKL, it cannot initiate the terminal differentiation of osteoclast precursors. In cell culture, osteoclast precursor cells need continuous exposure to both M-CSF and RANKL to form fully differentiated mature osteoclast. PGE2 treatment of

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murine osteoblastic cells had no effect on M-CSF mRNA expression [40]. The receptor for M-CSF is the product of the protooncogene c-fms [100]. This receptor, which is also known as CSF-1R, mediates responses through activation of tyrosine kinase [95]. Recently, mice lacking CSF-1R were generated and their phenotype was similar to that of the op/op mouse [100]. As with a number of immune cells, costimulatory molecules are involved in osteoclast formation. Two costimulatory receptors have been identified as being involved in osteoclast formation. These are TREM-2 [101] and OSCAR [102], which are found on the surface of osteoclast precursor cells and for which cognate ligands are unknown. Costimulatory receptors interact with activator proteins, containing an immunotyrosinebased activation motif (ITAM), to mediate their responses [103]. In osteoclast TREM-2 associates with DAP12 [104] while OSCAR associates with FcRγ [105]. If both DAP12 and FcRγ are absent in mice, osteoclast formation is markedly inhibited [105–107].

IV. THE ROLE THAT PROINFLAMMATORY CYTOKINES HAVE IN BONE AND CARTILAGE METABOLISM The cytokines that have been most extensively studied for their ability to regulate bone and cartilage function are interleukin-1 (IL-1), tumor necrosis factor (TNF), and interleukin-6 (IL-6). These agents are proinflammatory cytokines that have potent effects in a variety of in vivo and in vitro assays. This section will focus on their actions in bone and cartilage. In addition, the role of other IL-6 family member cytokines will be briefly reviewed.

A. Effects of Interleukin-1 on Bone Interleukin-1 (IL-1) is encoded by two separate gene products, α and β, which have identical activities [108]. IL-1 was the first polypeptide mediator of immune cell function that was found to regulate bone resorption [109, 110]. It also increased prostaglandin synthesis in bone [110], an effect that may account for some of its resorptive activity. This response is mediated through its ability to increase production of cyclooxygenase 2 [111] and the effect does not appear to require nitric oxide synthesis [112]. IL-1 is the most potent peptide stimulator of in vitro bone resorption that has yet been identified [110]

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and it also has potent in vivo effects [113]. The in vitro effects of IL-1 on bone formation appear to be inhibitory [114–116]; although, it does stimulate DNA synthesis in both bone organ cultures and primary cultures of human bone cells [116, 117]. IL-1 is produced in bone [118] and IL-1 activity is present in bone marrow serum [119, 120]. Macrophages are a likely source of local bone IL-1 [121]. In addition, osteoblasts and osteoclasts may also produce it [122, 123]. IL-1 also appears to directly stimulate mature osteoclast to resorb [124]. A natural inhibitor to IL-1, IL-1 receptor antagonist (IL-1ra), is an analog of IL-1 that binds but does not activate the type 1 IL-1 receptor [125–127]. IL-1ra blocks the ability of IL-1 to stimulate resorption and PGE2 production in bone organ cultures [128]. Increased release of IL-1ra has been demonstrated from peripheral blood monocytes (PBM) of both normal and osteoporotic postmenopausal women [129]. Decreased levels of IL-1ra are also reported in the bone marrow of some women with a rapid-loss form of osteoporosis [130]. There are two known receptors for IL-1, type I and type II [131]. All known biologic responses to IL-1 appear to be mediated exclusively through the type I receptor [132]. Signaling through type I receptors involves activation of NF-κB and specific TNF receptor associated factors (TRAFs) [133, 134]. IL-1 receptor type I requires interaction with a second protein, interleukin-1 receptor accessory protein (IRAcP), to generate postreceptor signals [135–137]. IRAcP induces activation of interleukin-1 receptor-associated kinase (IRAK) [52]. Phosphorylated IRAK binds TRAF6 with subsequent downstream signaling. IL-1 receptor type II appears to have no agonist activity. Rather, there is convincing evidence that it is a decoy receptor, which prevents activation of IL-1 type I receptors [138]. IL-1 receptor type II can also synergize with IL-1ra to inhibit activation of the IL-1 receptor type I [139]. The role of IL-1 in estrogenmediated bone loss had been suspected from studies which demonstrated that the IL-1 antagonist IL-1ra blocked ovariectomy-induced bone loss [140], and was confirmed by studies demonstrating that mice lacking the IL-1 receptor type I (IL-1R1 −/−) did not lose bone mass with ovariectomy [141]. Studies of the regulation of IL-1 by estrogens in humans have been inconsistent. One group demonstrated that IL-1 levels in serum were increased 4 weeks after ovariectomy [142]. However, others failed to find a correlation between serum IL-1α, IL-1β, or IL-1ra levels and indices of bone turnover in either pre- or post-menopausal women [143] or between osteoporotic women and normals [144].

Production of IL-1 receptor type II, the decoy IL-1 receptor, is up-regulated by estrogen treatment [145, 146]. It is possible that estrogen regulates bone mass by increasing IL-1 receptor type II expression independent of any direct effects on IL-1 production. This response would decrease the ability of bone cells to respond to IL-1 and blunt the potent catabolic effects of IL-1 on bone mass.

B. Effects of Interleukin-1 on Cartilage IL-1 is a potent regulator of cartilage cell function. It inhibits cartilage cell replication, colony formation in soft agar and proteoglycan synthesis [147, 148], while it stimulates production of matrix metalloproteinases, which degrade cartilage collagen [149]. IL-1 also inhibited the production of cartilage-specific collagens [150] and it regulated expression of 1,25-dihydroxyvitamin D receptors and type X collagen production in growth plate chondrocytes but had little effect on type II collagen synthesis [151]. IL-1 may be involved in the regulation of growth plate cartilage since it is made by these cells [152]. Production of IL-1 in rat growth plate cartilage was altered by the vitamin D status of the animals [153]. This mechanism may be involved in growth. However, it is not critical since mice that cannot respond to IL-1 grow normally [154]. In vitro, IL-1 and tumor necrosis factor (TNF) act synergistically to inhibit the growth of cultured long bones and this response appears mediated by decreased chondrocyte proliferation and increased apoptosis [155].

C. Effects of Tumor Necrosis Factor on Bone Like IL-1, tumor necrosis factor (TNF) is a family of two related polypeptides (α and β) that are separate gene products [156–160]. TNFα and β have similar biologic activities and are both potent stimulators of bone resorption [110, 161, 162]. TNF also enhances the formation of osteoclast-like cells in bone marrow culture [163]. Therefore, it appears to regulate osteoclast precursor cell differentiation. TNFα was produced by human osteoblast-like cell cultures [164] and its production was stimulated by IL-1, GM-CSF and lipopolysaccharide, but not by PTH, 1,25(OH)2 vitamin D, or calcitonin. Recently, TNF was shown to stimulate osteoclast formation directly in an in vitro culture system [124, 165]. This effect was independent of RANK actions since it occurred in cells from RANK-deficient mice. However, the functional significance of this finding is questionable because in vivo administration of TNF to

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RANK-deficient mice caused only an occasional osteoclast to form [166]. Like IL-1, TNF binds to two cell surface receptors, the TNF receptor 1 or p55 and the TNF receptor 2 or p75 [167]. In contrast to IL-1, both receptors transmit biologic responses. Mice deficient in either or both TNF receptors have been made [168–170]. All of these animals appear healthy and breed normally, but lack selective immune responses. Bones from mice that lack either IL-1 receptor type I or TNF receptor 1 are similar to those of wild-type mice, except for a 36% increase in the total bone area of calvaria from IL-1 receptor type I-deficient mice, compared to wild-type animals [154]. Mice deficient in TNF (TNF −/−) fail to lose bone mass after ovariectomy [171]. This finding appears significant because production of TNF by T lymphocytes appears responsible for some of the bone loss that occurs in mice after ovariectomy [172]. TNF appears to have direct effects on osteoclast formation independent of RANKL [124]. However, this response requires that the osteoclast precursor cells be previously exposed to RANKL [173].

D. Effects of Tumor Necrosis Factor on Cartilage Like IL-1, TNFα stimulates production of degradative enzymes in cartilage and inhibits cartilage synthesis [174, 175]. Both TNF and IL-1 are implicated as mediators of inflammatory arthritis [176]. In costal chondrocytes TNF decreased alkaline phosphatase and DNA synthesis [177]. In vivo fracture healing in rat ribs was inhibited by TNFα treatment [178]. This effect was due to a decrease in cartilaginous callus formation and, possibly, a decrease in the differentiation of mesenchymal cells into chondroblasts.

E. Effects of Interleukin 6 on Bone IL-6, like IL-1 and TNF, has a wide variety of effects on immune cell function and on the replication and differentiation of other cell types [179, 180]. The receptor for IL-6 is composed of two parts: a specific IL-6 binding protein (IL-6 receptor), which can be either membrane bound or soluble, and gp-130, an activator protein that is common to a number of cytokine receptors [181]. Production of the specific IL-6 receptor may be regulated, since it is not expressed on bone cells at all times [182]. The ability of IL-6 to stimulate bone resorption in vitro is variable and depends on the assay system that is examined [183–186]. The reasons for these discrepancies are unknown. It appears that a major effect of IL-6 is to

regulate the differentiation of osteoclast progenitor cells into mature osteoclast [187, 188]. In an in vitro model of osteoclast differentiation from human bone marrow, IL-6 was found to be a potent stimulus of new osteoclast-like cell development by a mechanism that was also dependent on IL-1 [189]. In contrast, in a murine in vitro system, IL-6 was only effective when soluble IL-6 receptor was added to the cultures [182]. Implantation of Chinese hamster ovary (CHO) cells, which were genetically engineered to express murine IL-6, into nude mice produced a syndrome of hypercalcemia, cachexia, leukocytosis, and thrombocytosis [190]. The effects of IL-6 on resorption in this model were weak, but were significantly potentiated when the animals were also treated with PTHrP [191]. A major effect of IL-6 in these in vivo models was to increase the number of early osteoclast precursors (CFU-GM) in the marrow. IL-6 may mediate some of the increased bone resorption and bone pathology that is seen in the clinical syndromes of Paget’s disease [192], hypercalcemia of malignancy [193], fibrous dysplasia [194], giant cell tumors of bone [195], and Gorham–Stout disease [196]. Ovariectomy-induced bone loss in mice has been associated with increased IL-6 production [197] and mice deficient in IL-6 failed to lose bone after ovariectomy [198].

F. Effects of Interleukin 6 on Cartilage IL-6 is produced in cartilage in response to treatment with inflammatory cytokines such as IL-1 and TNF [176]. IL-6 production is increased by treatment with growth hormone or insulin-like growth factor-1 (IGF-1) in growth plate chondrocyte cultures [199]. However, in human articular cartilage cultures IGF-1 had no effect on IL-6 production [200]. IL-6 is not critical for skeletal growth since IL-6 deficient mice grow normally [201]. IL-6 also enhances cartilage production of tissue inhibitor of metalloproteinase 1 (TIMP-1), a factor that blocks the activity of metalloproteinases, which degrade cartilage [202, 203] (see also Chapter 11).

G. Effects of Other Interleukin-6 Family Members on Bone IL-6 is a member of a group of cytokines that share the gp-130 activator protein in their receptor complex [204, 205]. Each family member utilizes unique ligand receptors to generate specific binding. Besides IL-6, the cytokines of this family include interleukin 11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM),

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ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1). Except for CT-1, receptors for all other IL-6 family members have been detected in bone marrow stromal or osteoblastic cells [206]. In addition, IL-11-specific receptors are present in osteoclast-like cells that are generated in vitro. Signal transduction through these receptors utilizes the JAK/STAT pathway [181]. Leukemia inhibitory factor (LIF) is produced by bone cells in response to a number of resorption stimuli [207–209]. However, production can be variable and depends on the model system that is being studied. The effects of LIF on bone resorption are also variable. In a number of in vitro model systems, LIF stimulated resorption by a mechanism that is prostaglandin dependent [210] while, in other in vitro assays, it had inhibitory effects [211, 212]. Up-regulation of RANKL production seems to be the mechanism by which LIF stimulates resorption in bone organ cultures, although the role of prostaglandins in this model is unknown [213]. Mice that lack the specific LIF receptor and, hence, cannot respond to LIF, have reduced bone volume and a six-fold increase in osteoclast numbers [214]. The role of IL-6 family members in osteoclast formation has been re-examined in the light of data demonstrating that mice lacking the gp-130 activator protein have an increased number of osteoclasts compared to wild-type animals [215]. Since gp-130 is an activator of signal transduction for all members of the IL-6 family, this result argues that at least some IL-6 family members inhibit osteoclast formation and bone resorption. The mechanism by which these effects occur were recently investigated in mice that were deficient in signaling through either the gp-130-mediated STAT 1/3 pathway or the SHP2/Ras/MAPK pathway [216]. In mice deficient in STAT 1/3 signaling premature growth plate closure reduced bone length. In SHP2/Ras/MAPK deficient mice osteoclast were increased. Crossing IL-6 deficient mice with mice deficient in gp-130-mediated SHP2/Ras/MAPK signaling decreased osteoblasts without affecting the increase in osteoclast. These results demonstrate that the gp-130-mediated STAT 1/3 pathway is a major regulator of chondrocyte differentiation while gp-130mediated SHP2/Ras/MAPK signaling is an inhibitor of osteoclastogenesis.

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