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Pathogenesis of hyperostosis: A key role for mesenchymatous cells?
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Pathogenesis of hyperostosis: A key role for mesenchymatous cells? Jean-Marie Berthelot ∗ , Benoît Le Goff , Yves Maugars Service de rhumatologie, Hôtel-Dieu, CHU de Nantes, 44093, Nantes cedex 01, France
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Article history: Accepted 28 February 2013 Available online xxx Keywords: Skeletal hyperostosis Forestier’s disease Hyperostosis Diffuse idiopathic skeletal Calcifications Adipocytokines Leptin Adiponectin Mesenchymal cells Enthesopathy
a b s t r a c t The similarities between diffuse idiopathic skeletal hyperostosis (DISH) and some forms of ankylosing spondylitis suggest shared pathogenic mechanisms. Entheseal ossification progresses at the same rate in the two conditions, and spondyloarthritis was the first diagnosis considered in several families with genetically determined early-onset DISH. However, DISH may be a heterogeneous condition, as the presence of peripheral calcifications in some families suggests pathogenic similarities with several animal models combining entheseal ossification and peripheral calcifications, as well as with X-linked familial hypophosphatemia and dentin-matrix-protein mutations. In the far more common presentation of hyperostosis without calcifications, entheseal ossification may be related to abnormal osteoblastic differentiation of mesenchymatous stem cells normally found around the intervertebral disks, in the vertebral periosteum, and in the anterior and posterior longitudinal ligaments. The many factors suspected of promoting this abnormal differentiation include bone morphogenetic proteins (BMPs), retinoids, and various hormonal factors; in addition, adipokines such as leptin are the focus of growing interest based on the well-documented association between DISH and obesity. Confirmation of the role for mesenchymatous cells in DISH should encourage investigations of mesenchymatous cells as possible pathogenic contributors to the entheseal abnormalities seen in spondyloarthritis. These cells normally exert immunosuppressive effects, which may be subverted in spondyloarthritis, notably by a T-cell population that homes specifically to the entheses. © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Although TNF␣ antagonists are extremely effective against the clinical manifestations of spondyloarthritides (SpAs) [1], they seem unable to slow the rate of ankylosis. This observation is galvanizing research into the mechanisms that produce syndesmophytes (vertical spicules, usually thin, developed along the outer edge of the anulus and sometimes extending to the supra- or infrajacent vertebra). Entheseal inflammation does not seem required: thus, in diffuse idiopathic skeletal hyperostosis (DISH) [2], the corner sign seen by magnetic resonance imaging (MRI) before ossifications develop is usually related to fatty infiltration, and not to inflammation. In addition, inflammatory forms of SpA without ossifications have been described [3]. Several recent studies indicate that entheseal inflammation and ossification are independent from each other and that ossification may result from repeated stress to the entheses [4]. Thus, the mechanisms underlying ossification in SpA and DISH may share similarities, a possibility that is further supported
∗ Corresponding author. Tel.: +33 2 40 08 48 22x801; fax: +33 2 40 08 48 30. E-mail address: [email protected] (J.-M. Berthelot).
by the comparable rate of ossification in the two conditions. In a German study comparing 146 patients with SpA and 141 with DISH, the rate of progression of the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) was not significantly different between the two groups (3.3 ± 4.2 versus 4.1 ± 9.5, i.e. a mean of +1.3 point/year) [5]. In this study, both syndesmophytes and osteophytes (coarser ossifications that tend toward the horizontal and form at the corners of a joint or degenerated disk) were documented in both conditions. Thus, syndesmophytes were more common in the SpA group (5.7 ± 5.5 per patient) but were also seen in the DISH group (2.7 ± 2.8 per patient) and, on the other hand, osteophytes were only slightly less numerous in patients with SpA (1.0 ± 1.4 per patient) than in patients with DISH (1.4 ± 1.8 per patient) [5]. In addition, the presentations in late-onset SpA and axial psoriatic arthritis can closely resemble DISH. These data suggest that valuable lessons may be learned from recent insights into DISH pathogenesis, despite the limited functional impact of DISH compared to SpAs (ankylosis of the vertebral and costovertebral joints is not factored into the mSASSS and is absent or minimal in DISH but causes much of the spinal stiffness seen in SpAs). We will start by discussing diagnoses that must be differentiated from ankylosing SpAs and DISH, as their investigation might generate new research hypotheses.
1297-319X/$ – see front matter © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2013.03.013
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Table 1 Other causes of diffuse ossification of vertebral and other ligaments. Ossification of the posterior longitudinal ligament (OPLL) Early-onset hyperostosis of the cervical spine and hips Ossification of the cervical vertebral ligaments with peripheral calcifications Combined hyperostosis and chondrocalcinosis in the Azores Fluorosis Long-term retinoid therapy Acromegaly Ochronosis X-linked familial hypophosphatemia Hypophosphatemia related to dentin matrix protein (DMP-1) mutations Hypoparathyroidism and pseudohypoparathyroidism Achondroplasia
Table 2 Co-factors involved in the pathogenesis of diffuse idiopathic skeletal hyperostosis (DISH). Various genetic factors Toxic agents containing fluoride, bexarotene, and other retinoids Hormones: GH, IGF-1, and adipokines including leptin and adiponectin Activation and differentiation of mesenchymatous cells under the influence of tensile loading and of fibronectin and BMP-2
2. Other conditions known to cause vertebral ligament ossification
patients with vertebral ligament ossification and a diagnosis of SpA or DISH, a finding of painless ossifications in family members should prompt phosphate and calcium assays [10]. In clinical research, there is even greater reason to evaluate phosphate and calcium metabolism, as calcifications and or phosphate/calcium abnormalities are found in some animal models of DISH (see below).
2.1. Without peripheral calcifications
3. Pathogenesis of diffuse idiopathic skeletal hyperostosis
In Japan, up to 4% of individuals in the general population have ossification of the posterior longitudinal ligament (OPLL) predominating at the cervical spine, a prevalence nearly 80-fold that seen in Europe [6] (Table 1). DISH is also more common in Japan, suggesting a relationship between the two conditions. Furthermore, nearly one-fourth of patients with OPLL also have ossification of the anterior longitudinal ligament. Nevertheless, early hyperostosis is not confined to Asian populations: severe cervical-spine hyperostosis starting before 25 years of age, without involvement of the thoracic or lumbar spine, has been reported in several members of a British family, who also had marked ossifications about the hips [7]. Some of these patients were erroneously diagnosed with SpA, although they tested negative for HLA-B27 and had no sacroiliac joint involvement.
3.1. Dog models DISH occurs with advancing age in 1% to 3% of large non-human primates (such as baboons and gorillas) and in many other mammals (including bears, camels, horses, bison, and whales) (Table 2). DISH may be the oldest documented disease, as evidence of the disease has been found in dinosaur skeletons [13]. The most useful animal models are probably dogs. As with humans, canine hyperostosis is more common in males and with advancing age [14]. On average, hyperostosis occurs in 4% of dogs, with differences across breeds. Among boxers, however, 40% develop hyperostosis. Thus, genetic studies in boxers might provide valuable insights, particularly as there is no predisposition to metabolic syndrome in this breed. 3.2. Hyperostosis with calcifications in animals
2.2. With peripheral calcifications Patients in other families have been mistakenly diagnosed with SpA based on the combined presence of cervical ligament ossifications and peripheral calcifications [8]. An association between hyperostosis and chondrocalcinosis, with sacroiliac joint involvement, has been reported in 12 families in the Azores [9]. These families had fairly atypical forms of chondrocalcinosis, with both extraarticular ectopic calcifications and fibrocartilage deposits: thus, of 103 individuals in these 12 families, 70 had soft-tissue calcifications but only 12 had typical chondrocalcinosis with pyrophosphate crystals identified in knee effusions. Sclerosis or ankylosis of the sacroiliac joints was a feature in 15% of patients, mistakenly suggesting SpA in some cases, particularly given the young age at onset of the clinical and radiological abnormalities (mean age at diagnosis, 38 years) [9]. Other conditions that can induce spinal ossifications resembling hyperostosis and/or some forms of SpA (such as axial psoriatic arthritis) include fluorosis, long-term retinoid therapy, acromegaly, ochronosis, and several disorders responsible for phosphate and calcium abnormalities. Vertebral ligament ossification and fullfledged DISH (with cranial hyperostosis in some patients) are possible complications of X-linked familial hypophosphatemia [10] and of other genetic hypophosphatemias such as the autosomal recessive disease caused by mutations in dentin matrix protein-1 (DMP-1), which is expressed in osteoblasts and osteocytes [11]. Hypoparathyroidism and pseudohypoparathyroidism can also result in vertebral ligament ossification, and short stature with proportionate growth may be present in these conditions [12]. Disproportionate short stature occurs in achondroplasia, another cause of vertebral ligament ossification. Therefore, in
That several human diseases are associated with both ectopic calcifications and hyperostosis is worthy of note. Several animal models are also characterized by a combination of calcifications (central or peripheral) and vertebral ligament ossification. Mice lacking equilibrative nucleoside transporter-1 (ENT-1) – a protein that carries nucleosides through the cell membrane – develop lesions closely similar to hyperostosis at the thoracic spine (with subsequent extension to the cervical and lumbar spine) and calcifications of various tissues (chiefly the intervertebral disks and chondrosternal junctions), and they also exhibit high blood levels of inorganic pyrophosphates [15]. 3.3. Other syndromes characterized by vertebral hyperostosis The MURCS association is an atypical form of Mayer-RokitanskyKuster-Hauser syndrome combining Müllerian duct aplasia, renal dysplasia, and cervicothoracic skeletal abnormalities. Severe spinal hyperostosis is present in some patients and may be combined with malformations of the occipitocervical junction [16]. The diseasesusceptibility genes have not yet been identified. WNT4 mutations have been found in some patients but do not seem to be the main cause. 3.4. Role for toxic agents in inducing focal hyperostosis Heterotopic ossifications are not always due to genetic abnormalities: other causes include trauma (as in myositis ossificans) and neurological disorders [17]. An unusual case of exuberant ossifications about multiple fracture sites was reported in a 33year-old man in whom the only potential risk factor was prolonged
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inhalation during the accident responsible for the fractures of high concentrations of an aerosol propellant (1,1-difluoroethane [DFE]) containing fluoride (C2 H4 F2 ) [18]. Spinal hyperostosis resembling DISH has been reported after long-term exposure to bexarotene [19], an anticancer agent used to treat breast cancer, lung cancer, and Kaposi’s sarcoma and capable of inducing amyloid deposit regression in murine models. Bexarotene activates the -retinoid receptor, and its ability to induce ossifications probably involves mechanisms similar to those triggered by retinoids. Long-term use of the retinoid etretinate to treat severe acne or erythrodermic psoriasis can induce hyperostosis along the joint capsules. These ossifications can cause joint stiffness, particularly at the hips, causing an inability to walk [20]. 3.5. Dickkopf-related protein-1 (DKK-1) In one study, serum levels of the osteoblast inhibitor DKK-1 were significantly lower in 37 patients with DISH than in 22 healthy age- and sex-matched controls (P < 0.0001). In addition, the lowest DKK-1 levels were associated with the greatest severity of spinal hyperostosis independently from age, sex, bone turnover markers, and bone mineral density [21]. However, another study failed to replicate this finding [22]. Rather than osteoblast dysfunction, abnormal differentiation of osteoblast precursors, most notably mesenchymous stem cells, may be central to the pathogenesis of DISH according to several recent studies (see below). 3.6. Genetic studies of patients with ossification of the posterior longitudinal ligament (OPLL): no convincing results to date OPLL frequently runs in families, with a pattern suggesting autosomal inheritance. A role for genetic co-factors is further supported by the high level of concordance in twins [23]. The gene or genes involved were first believed to be located between the Class II HLA genes and the collagen type 11 gene (COL11A2) [24]. Studies failed to confirm this possibility, and other collagen genes were therefore investigated. A study of seven COL6A1 polymorphisms in 97 Japanese and 96 Czech patients with OPLL versus 298 Japanese and 96 Czech controls showed overrepresentation of an intron polymorphism in the Japanese patients but not in the Czech patients. This finding may therefore be ascribable to chance, although abnormalities in COL6A1 are believed to promote the development of OPLL [25]. The most comprehensive study to date evaluated 109 polymorphisms of 35 candidate genes in 711 patients with OPLL and 896 controls [26]. The results failed to confirm any of the previously suspected associations (COL11A2, nucleotide pyrophosphatase gene [NPPS], and transforming growth factor 1 gene [TGFB1]). The only significant finding was a correlation between OPLL and a TGFB3 intron polymorphism (P = 0.00040) [26]. A role in OPLL is suspected for the vitamin D receptor gene and for genes encoding various cytokines and growth factors, chiefly the bone morphogenetic proteins (BMPs), but awaits confirmation [27]. The discrepancies across study results may be ascribable to the heterogeneity of OPLL, as strongly suggested by the fairly large number of animal models of OPLL. Thus, the identification of one or more susceptibility genes for OPLL may not be relevant to all forms of DISH, as DISH may also be a heterogeneous disease. In addition, whereas a fibroblast growth factor-1 (FGF-1) receptor polymorphism is associated with OPLL, a polymorphism in the FGF2 gene seems associated with DISH and another FGF2 polymorphism with ossification of the ligamentum flavum [28]. Nevertheless, a continuum probably exists between OPLL and some forms of DISH, as obesity and hyperinsulinism are risk factors for both conditions [27].
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3.7. Links between diffuse idiopathic skeletal hyperostosis and growth hormone Elevated serum levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) have been reported in patients with DISH compared to controls [29]. These elevated levels were not related to body mass index (BMI) [30] or presence of diabetes [31]. Only the GH levels correlated with joint and muscle pain and with stiffness [29]. GH elevations of similar magnitude were found in patients with rheumatoid arthritis, osteoarthritis, fibromyalgia, and joint laxity. Therefore, GH is probably not a major pathogenic factor in DISH. 3.8. Role for metabolic syndrome in the pathogenesis of diffuse idiopathic skeletal hyperostosis Strong associations were reported many years ago between the development of DISH and diabetes, familial diabetes, or hypertension. These associations have been confirmed in a few case-control studies in which the controls were healthy individuals or patients with osteoarthritis [32]. Hyperostosis seems more closely associated with type II than with type I diabetes [33]. DISH increases the cardiovascular risk independently from BMI and to a lesser degree. In a study of 47 patients with DISH matched to 48 controls, the 10-year risk of developing cardiovascular disease was very significantly increased in the patients (P = 0.007), although the serum lipid profiles were similar in the two groups [34]. In the same study, the prevalence of metabolic syndrome, which correlated strongly with excessive body weight, was 3.81 times higher in the group with DISH. Studies of carbohydrate and lipid metabolism in non-diabetic patients with DISH failed to identify major abnormalities compared to controls: the non-esterified triglyceride level was slightly lower and the insulin index minimally decreased, but no differences were found for IGF-1, IGF-1 binding protein 3 (IGF-BP3), uric acid, or cholesterol [31]. It would therefore be of interest to investigate the potential pathogenic role in DISH for adipokines, since these molecules are not only associated with metabolic syndrome, but also affect bone differentiation. 3.9. Role for adipokines in the pathogenesis of diffuse idiopathic skeletal hyperostosis Leptin levels are increased in patients with OPLL [35] and correlate with the severity and extent of the ossifications [36]. In vitro leptin exposure of cells from the ossified ligaments does not increase alkaline phosphatase activity or collagen synthesis [35]. However, the leptin receptor is expressed in the longitudinal ligaments. Thus, in conjunction with other stimuli, leptin may contribute to the ossification process in DISH, for instance by stimulating mesenchymatous cells. Leptin and its receptor are expressed in the anulus, where the leptin levels increase with advancing age [37]. Whereas mesenchymatous cell differentiation to adipocytes was previously thought to be the main effect of leptin, osteoinducing potential was unexpectedly documented in a recent study [38]. In addition, leptin is released within osteophytes in patients with osteoarthritis [39]. Among the other adipokines, adiponectin also deserves investigation, since it promotes osteoblastic differentiation of mesenchymatous cells [40], which are found in abundance in the entheses. 3.10. Role for mesenchymatous cells in the pathogenesis of diffuse idiopathic skeletal hyperostosis A key role for mesenchymatous cells in entheseal physiology and pathology has been established in murine models of enthesopathy. Thus, the speed and quality of lesion repair were
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greater after mesenchymatous cell injection than after chondrocyte injection [41]. Other studies evaluated the optimal conditions for differentiation of marrow mesenchymatous cells to tenocytes, chondrocytes, or bone cells according to their position in the enthesis. The results showed that mesenchymatous cell differentiation toward a tendon or bone phenotype depended on the degree of tensile loading: higher tensile loads (chiefly > 70–90 Pa) promoted osteogenic differentiation. However, this differentiation is also strongly influenced by paracrine signals (including the collagen-1 or fibronectin concentration), at least in the absence of strong tensile loads. High fibronectin concentrations promote osteogenic differentiation, whereas high collagen-1 concentrations inhibit osteogenic differentiation and promote differentiation to tenocytes [42]. These signals seem to converge toward BMP-2 production and the Smad8 signaling pathway, which strongly inhibits differentiation to osteoblasts [43] and promotes the development of tendon tissue within the enthesis [44]. Recent studies established that the abnormal bone production responsible for osteophyte formation was associated with the presence within osteophytes of mesenchymatous cells receiving abnormal signals from the adjacent cartilage and/or bone (excessive tensile loading and biological signals). Human osteophytes have been found to contain cells exhibiting a mesenchymatous cell phenotype (CD90+, CD105+, CD73+) and probably originating in the periosteum. These cells exhibit greater proliferative potential than do the other osteoblastic precursors such as marrow mesenchymatous cells [45]. They age more slowly and express larger amounts of BMP-2 compared to their marrow counterparts [46]. Proliferation of these periosteal mesenchymatous cells starts very early in murine models of experimental destructive arthritis (on day 3) and is not inhibited by blocking TNF or the RANK-RANKL pathway [47]. In all likelihood, these periosteal cells are at the origin of the abnormal ossifications in DISH. In rabbits, mesenchymatous cell injection into the intervertebral disks (after incision to induce degenerative changes) resulted in the development of large anterolateral osteophytes. The injected cells were identifiable within the osteophytes, suggesting a role in the abnormal bone formation. In-depth studies of cell migration outside the disks rare needed, and their results will determine whether intradiscal injections of autologous mesenchymal cells can be considered a potential treatment for human degenerative disk disease [48]. In humans, mesenchymatous cells have been identified in intervertebral disks in individuals aged 35 to 70 years [49], chiefly in a peripheral location. The main niche for progenitor mesenchymatous cells may be the junction of the anulus, vertebral ligaments, and endplate perichondrium [50]. From this site, the cells migrate to the nucleus and anulus [51] and may then travel to the tissues surrounding the disk. This topographic distribution is similar to that seen in the periosteum, the source of the mesenchymatous cells found in osteophytes [47]. In one of the murine models of OPLL, the nucleus cells first release excessive amounts of mucopolysaccharides, after which a tear occurs in the annulus; then, other cell types proliferate in the anulus and subsequently invade the posterior longitudinal ligament, where they induce hypervascularization and, above all, metaplasia to osteoblasts of the mesenchymatous cells already present within the ligaments [52]. Anterolateral disk tears may not constitute a prerequisite to the development of hyperostosis, however: mesenchymatous stem cells identified within the ligamentum flavum may be capable of differentiation to adipocytes, chondrocytes, or osteoblasts [53]; and mesenchymatous cells have been identified in various vertebral ligaments in eight Japanese patients undergoing surgery for lumbar spinal stenosis or OPLL. These cells were associated with the collagen matrix or small-vessel pericytes within the ligaments and were capable of in vitro differentiation to adipocytes, chondrocytes and, above all, bone cells
[54]. Taken in concert, these findings suggest that mesenchymatous cells at the periphery of the intervertebral disks and/or within the vertebral ligaments may play a central role in the pathogenesis of DISH. 3.11. Possible means of preventing mesenchymatous cell differentiation to osteoblasts The proliferation of spinal mesenchymatous cells and their transformation to fibroblasts, myoblasts, or osteoblasts under the influence of TGF-, which inhibits their differentiation to adipocytes, can be blocked by the TGF- inhibitor trichostatin A [53]. Trichostatin A might therefore hold promise for the treatment of lumbar spinal stenosis and some forms of DISH. However, the many other factors involved in mesenchymatous stem cell differentiation also hold potential s treatment targets. They include growth factors; hormones such as 1,25-dihydroxyvitamine D2 + D3, parathyroid hormone, and insulin; retinoids; and various BMPs including BMP-2 [55]. Other suggested treatments for DISH are BMP inhibitors (e.g. Noggin), BMP receptors [2], and nuclear agonists of the retinoic acid gamma-receptor [56]. In addition, as mentioned above, adipokines such as leptin might constitute treatment targets in both DISH and SpAs, since IL-17 increases the production of leptin by human marrow mesenchymatous cells [57]. 4. Conclusion Although the risk of severe upper airway and neurological complications associated with DISH is sufficient reason to investigate the pathogenesis of this condition [2], improved knowledge of DISH would probably lead to novel hypotheses regarding the mechanisms of the entheseal lesions seen in SpAs. Recent evidence suggests that some CD4-CD8- T-cells that strongly express the IL23 receptor are characterized by highly selective homing to the eye, aortic arch, and entheses [58]. Research into interactions between entheseal mesenchymatous cells and this T-cell subset might produce valuable insights, given the immunoregulating properties of mesenchymatous cells and recent evidence of a role for these cells in the ossification process in DISH. It would be unfortunate to confine studies into the pathogenesis of ankylosis in SpAs to osteoblasts and bone turnover markers, particularly as this line of research has so far failed to produce compelling results [2,59]. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Claudepierre P, Wendling D, Breban M, et al. Ankylosing spondylitis, spondyloarthropathy, spondyloarthritis, or spondylarthritis: what’s in a name? Joint Bone Spine 2012;79:534–5. [2] Mazières B. Diffuse idiopathic skeletal hyperostosis (Forestier-Rotes-Querol disease): what’s new? Joint Bone Spine 2013, doi:10.1016/j.jbspin.2013.02.011. [3] Wendling D, Prati C, Claudepierre P, et al. Non-radiographic spondyloarthritis: a theoretical concept or a real entity? Joint Bone Spine 2012;79:531–3. [4] Braem K, Deroose CM, Luyten FP, et al. Inhibition of inflammation but not ankylosis by glucocorticoids in mice: further evidence for the entheseal stress hypothesis. Arthritis Res Ther 2012;14:R59, doi:10.1186/ar3772. [5] Baraliakos X, Listing J, Buschmann J, et al. A comparison of new bone formation in patients with ankylosing spondylitis and patients with diffuse idiopathic skeletal hyperostosis: a retrospective cohort study over six years. Arthritis Rheum 2012;64:1127–33. [6] Ono M, Russell WJ, Kudo S, et al. Ossification of the thoracic posterior longitudinal ligament in a fixed population. Radiological and neurological manifestations. Radiology 1982;143:469–74. [7] Corman G, Jawad AS, Chikanza I. A family with diffuse idiopathic skeletal hyperostosis. Ann Rheum Dis 2005;64:1794–5.
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[35] -Shirakura Y, Sugiyama T, Tanaka H, et al. Hyperleptinemia in female patients with ossification of spinal ligaments. Biochem Biophys Res Commun 2000;267:752–5. [36] Ikeda Y, Nakajima A, Aiba A, et al. Association between serum leptin and bone metabolic markers, and the development of heterotopic ossification of the spinal ligament in female patients with ossification of the posterior longitudinal ligament. Eur Spine J 2011;20:1450–8. [37] Zhao CQ, Liu D, Li H, et al. Expression of leptin and its functional receptor on disc cells: contribution to cell proliferation. Spine (Phila Pa 1976) 2008;33: E858–64. [38] Turner RT, Kalra SP, Wong CP, et al. Peripheral leptin regulates bone formation. J Bone Miner Res 2012, doi:10.1002/jbmr.1734. [39] Presle N, Pottie P, Dumond H, et al. Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis. Contribution of joint tissues to their articular production. Osteoarthritis Cartilage 2006;14:690–5. [40] Lee HW, Kim SY, Kim AY, et al. Adiponectin stimulates osteoblast differentiation through induction of COX2 in mesenchymal progenitor cells. Stem Cells 2009;27:2254–62. [41] Nourissat G, Diop A, Maurel N, et al. Mesenchymal stem cell therapy regenerates the native bone-tendon junction after surgical repair in a degenerative rat model. PLoS One 2010;18:e12248. [42] Rui YF, Lui PP, Ni M, et al. Mechanical loading increased BMP-2 expression which promoted osteogenic differentiation of tendon-derived stem cells. J Orthop Res 2011;29:390–6. [43] Sharma RI, Snedeker JG. Paracrine interactions between mesenchymal stem cells affect substrate driven differentiation toward tendon and bone phenotypes. PLoS One 2012;7:e31504. [44] Shahab-Osterloh S, Witte F, Hoffmann A, et al. Mesenchymal stem celldependent formation of heterotopic tendon-bone insertions (osteotendinous junctions). Stem Cells 2010;28:1590–601. [45] Singh S, Jones BJ, Crawford R, et al. Characterization of a mesenchymal-like stem cell population from osteophyte tissue. Stem Cells Dev 2008;17:245–54. [46] Singh S, Dhaliwal N, Crawford R, et al. Cellular senescence and longevity of osteophyte-derived mesenchymal stem cells compared to patient-matched bone marrow stromal cells. J Cell Biochem 2009;108:839–50. [47] Schett G, Stolina M, Dwyer D, et al. Tumor necrosis factor alpha and RANKL blockade cannot halt bony spur formation in experimental inflammatory arthritis. Arthritis Rheum 2009;60:2644–54. [48] Vadalà G, Sowa G, Hubert M, et al. Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation. J Tissue Eng Regen Med 2012;6:348–55. [49] Brisby H, Papadimitriou N, Brantsing C, et al. The presence of local mesenchymal progenitor cells in human degenerated intervertebral discs and possibilities to influence these in vitro: a descriptive study in humans. Stem Cells Dev 2013;22:804–14, doi:10.1089/scd.2012.0179. [50] Henriksson H, Thornemo M, Karlsson C, et al. Identification of cell proliferation zones, progenitor cells and a potential stem cell niche in the intervertebral disc region: a study in four species. Spine (Phila Pa 1976) 2009;34:2278–87. [51] Henriksson HB, Svala E, Skioldebrand E, et al. Support of concept that migrating progenitor cells from stem cell niches contribute to normal regeneration of the adult mammal intervertebral disc: a descriptive study in the New Zealand white rabbit. Spine (Phila Pa 1976) 2012;37:722–32. [52] Uchida K, Yayama T, Sugita D, et al. Initiation and progression of ossification of the posterior longitudinal ligament of the cervical spine in the hereditary spinal hyperostotic mouse (twy/twy). Eur Spine J 2012;21:149–55. [53] Chen YT, Wei JD, Wang JP, et al. Isolation of mesenchymal stem cells from human ligamentum flavum: implicating etiology of ligamentum flavum hypertrophy. Spine (Phila Pa 1976) 2011;36:E1193–200. [54] Asari T, Furukawa K, Tanaka S, et al. Mesenchymal stem cell isolation and characterization from human spinal ligaments. Biochem Biophys Res Commun 2012;417:1193–9. [55] Li H, Jiang LS, Dai LY. Hormones and growth factors in the pathogenesis of spinal ligament ossification. Eur Spine J 2007;16:1075–84. [56] Pavlou G, Kyrkos M, Tsialogiannis E, et al. Pharmacological treatment of heterotopic ossification following hip surgery: an update. Expert Opin Pharmacother 2012;13:619–22. [57] Noh M. Interleukin-17A increases leptin production in human bone marrow mesenchymal stem cells. Biochem Pharmacol 2012;83:661–70. [58] Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces spondyloarthropathy by acting on ROR-␥t+ CD3 + CD4-CD8- entheseal resident T cells. Nat Med 2012;18:1069–76. [59] Coiffier G, Bouvard B, Chopin F, et al. Common bone turnover markers in rheumatoid arthritis and ankylosing spondylitis: a literature review. Joint Bone Spine 2012, doi:10.1016/j.jbspin.2012.08.004.
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Pathogenesis of hyperostosis: A key role for mesenchymatous cells? Jean-Marie Berthelot ∗ , Benoît Le Goff , Yves Maugars Service de rhumatologie, Hôtel-Dieu, CHU de Nantes, 44093, Nantes cedex 01, France
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Article history: Accepted 28 February 2013 Available online xxx Keywords: Skeletal hyperostosis Forestier’s disease Hyperostosis Diffuse idiopathic skeletal Calcifications Adipocytokines Leptin Adiponectin Mesenchymal cells Enthesopathy
a b s t r a c t The similarities between diffuse idiopathic skeletal hyperostosis (DISH) and some forms of ankylosing spondylitis suggest shared pathogenic mechanisms. Entheseal ossification progresses at the same rate in the two conditions, and spondyloarthritis was the first diagnosis considered in several families with genetically determined early-onset DISH. However, DISH may be a heterogeneous condition, as the presence of peripheral calcifications in some families suggests pathogenic similarities with several animal models combining entheseal ossification and peripheral calcifications, as well as with X-linked familial hypophosphatemia and dentin-matrix-protein mutations. In the far more common presentation of hyperostosis without calcifications, entheseal ossification may be related to abnormal osteoblastic differentiation of mesenchymatous stem cells normally found around the intervertebral disks, in the vertebral periosteum, and in the anterior and posterior longitudinal ligaments. The many factors suspected of promoting this abnormal differentiation include bone morphogenetic proteins (BMPs), retinoids, and various hormonal factors; in addition, adipokines such as leptin are the focus of growing interest based on the well-documented association between DISH and obesity. Confirmation of the role for mesenchymatous cells in DISH should encourage investigations of mesenchymatous cells as possible pathogenic contributors to the entheseal abnormalities seen in spondyloarthritis. These cells normally exert immunosuppressive effects, which may be subverted in spondyloarthritis, notably by a T-cell population that homes specifically to the entheses. © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Although TNF␣ antagonists are extremely effective against the clinical manifestations of spondyloarthritides (SpAs) [1], they seem unable to slow the rate of ankylosis. This observation is galvanizing research into the mechanisms that produce syndesmophytes (vertical spicules, usually thin, developed along the outer edge of the anulus and sometimes extending to the supra- or infrajacent vertebra). Entheseal inflammation does not seem required: thus, in diffuse idiopathic skeletal hyperostosis (DISH) [2], the corner sign seen by magnetic resonance imaging (MRI) before ossifications develop is usually related to fatty infiltration, and not to inflammation. In addition, inflammatory forms of SpA without ossifications have been described [3]. Several recent studies indicate that entheseal inflammation and ossification are independent from each other and that ossification may result from repeated stress to the entheses [4]. Thus, the mechanisms underlying ossification in SpA and DISH may share similarities, a possibility that is further supported
∗ Corresponding author. Tel.: +33 2 40 08 48 22x801; fax: +33 2 40 08 48 30. E-mail address: [email protected] (J.-M. Berthelot).
by the comparable rate of ossification in the two conditions. In a German study comparing 146 patients with SpA and 141 with DISH, the rate of progression of the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) was not significantly different between the two groups (3.3 ± 4.2 versus 4.1 ± 9.5, i.e. a mean of +1.3 point/year) [5]. In this study, both syndesmophytes and osteophytes (coarser ossifications that tend toward the horizontal and form at the corners of a joint or degenerated disk) were documented in both conditions. Thus, syndesmophytes were more common in the SpA group (5.7 ± 5.5 per patient) but were also seen in the DISH group (2.7 ± 2.8 per patient) and, on the other hand, osteophytes were only slightly less numerous in patients with SpA (1.0 ± 1.4 per patient) than in patients with DISH (1.4 ± 1.8 per patient) [5]. In addition, the presentations in late-onset SpA and axial psoriatic arthritis can closely resemble DISH. These data suggest that valuable lessons may be learned from recent insights into DISH pathogenesis, despite the limited functional impact of DISH compared to SpAs (ankylosis of the vertebral and costovertebral joints is not factored into the mSASSS and is absent or minimal in DISH but causes much of the spinal stiffness seen in SpAs). We will start by discussing diagnoses that must be differentiated from ankylosing SpAs and DISH, as their investigation might generate new research hypotheses.
1297-319X/$ – see front matter © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2013.03.013
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Table 1 Other causes of diffuse ossification of vertebral and other ligaments. Ossification of the posterior longitudinal ligament (OPLL) Early-onset hyperostosis of the cervical spine and hips Ossification of the cervical vertebral ligaments with peripheral calcifications Combined hyperostosis and chondrocalcinosis in the Azores Fluorosis Long-term retinoid therapy Acromegaly Ochronosis X-linked familial hypophosphatemia Hypophosphatemia related to dentin matrix protein (DMP-1) mutations Hypoparathyroidism and pseudohypoparathyroidism Achondroplasia
Table 2 Co-factors involved in the pathogenesis of diffuse idiopathic skeletal hyperostosis (DISH). Various genetic factors Toxic agents containing fluoride, bexarotene, and other retinoids Hormones: GH, IGF-1, and adipokines including leptin and adiponectin Activation and differentiation of mesenchymatous cells under the influence of tensile loading and of fibronectin and BMP-2
2. Other conditions known to cause vertebral ligament ossification
patients with vertebral ligament ossification and a diagnosis of SpA or DISH, a finding of painless ossifications in family members should prompt phosphate and calcium assays [10]. In clinical research, there is even greater reason to evaluate phosphate and calcium metabolism, as calcifications and or phosphate/calcium abnormalities are found in some animal models of DISH (see below).
2.1. Without peripheral calcifications
3. Pathogenesis of diffuse idiopathic skeletal hyperostosis
In Japan, up to 4% of individuals in the general population have ossification of the posterior longitudinal ligament (OPLL) predominating at the cervical spine, a prevalence nearly 80-fold that seen in Europe [6] (Table 1). DISH is also more common in Japan, suggesting a relationship between the two conditions. Furthermore, nearly one-fourth of patients with OPLL also have ossification of the anterior longitudinal ligament. Nevertheless, early hyperostosis is not confined to Asian populations: severe cervical-spine hyperostosis starting before 25 years of age, without involvement of the thoracic or lumbar spine, has been reported in several members of a British family, who also had marked ossifications about the hips [7]. Some of these patients were erroneously diagnosed with SpA, although they tested negative for HLA-B27 and had no sacroiliac joint involvement.
3.1. Dog models DISH occurs with advancing age in 1% to 3% of large non-human primates (such as baboons and gorillas) and in many other mammals (including bears, camels, horses, bison, and whales) (Table 2). DISH may be the oldest documented disease, as evidence of the disease has been found in dinosaur skeletons [13]. The most useful animal models are probably dogs. As with humans, canine hyperostosis is more common in males and with advancing age [14]. On average, hyperostosis occurs in 4% of dogs, with differences across breeds. Among boxers, however, 40% develop hyperostosis. Thus, genetic studies in boxers might provide valuable insights, particularly as there is no predisposition to metabolic syndrome in this breed. 3.2. Hyperostosis with calcifications in animals
2.2. With peripheral calcifications Patients in other families have been mistakenly diagnosed with SpA based on the combined presence of cervical ligament ossifications and peripheral calcifications [8]. An association between hyperostosis and chondrocalcinosis, with sacroiliac joint involvement, has been reported in 12 families in the Azores [9]. These families had fairly atypical forms of chondrocalcinosis, with both extraarticular ectopic calcifications and fibrocartilage deposits: thus, of 103 individuals in these 12 families, 70 had soft-tissue calcifications but only 12 had typical chondrocalcinosis with pyrophosphate crystals identified in knee effusions. Sclerosis or ankylosis of the sacroiliac joints was a feature in 15% of patients, mistakenly suggesting SpA in some cases, particularly given the young age at onset of the clinical and radiological abnormalities (mean age at diagnosis, 38 years) [9]. Other conditions that can induce spinal ossifications resembling hyperostosis and/or some forms of SpA (such as axial psoriatic arthritis) include fluorosis, long-term retinoid therapy, acromegaly, ochronosis, and several disorders responsible for phosphate and calcium abnormalities. Vertebral ligament ossification and fullfledged DISH (with cranial hyperostosis in some patients) are possible complications of X-linked familial hypophosphatemia [10] and of other genetic hypophosphatemias such as the autosomal recessive disease caused by mutations in dentin matrix protein-1 (DMP-1), which is expressed in osteoblasts and osteocytes [11]. Hypoparathyroidism and pseudohypoparathyroidism can also result in vertebral ligament ossification, and short stature with proportionate growth may be present in these conditions [12]. Disproportionate short stature occurs in achondroplasia, another cause of vertebral ligament ossification. Therefore, in
That several human diseases are associated with both ectopic calcifications and hyperostosis is worthy of note. Several animal models are also characterized by a combination of calcifications (central or peripheral) and vertebral ligament ossification. Mice lacking equilibrative nucleoside transporter-1 (ENT-1) – a protein that carries nucleosides through the cell membrane – develop lesions closely similar to hyperostosis at the thoracic spine (with subsequent extension to the cervical and lumbar spine) and calcifications of various tissues (chiefly the intervertebral disks and chondrosternal junctions), and they also exhibit high blood levels of inorganic pyrophosphates [15]. 3.3. Other syndromes characterized by vertebral hyperostosis The MURCS association is an atypical form of Mayer-RokitanskyKuster-Hauser syndrome combining Müllerian duct aplasia, renal dysplasia, and cervicothoracic skeletal abnormalities. Severe spinal hyperostosis is present in some patients and may be combined with malformations of the occipitocervical junction [16]. The diseasesusceptibility genes have not yet been identified. WNT4 mutations have been found in some patients but do not seem to be the main cause. 3.4. Role for toxic agents in inducing focal hyperostosis Heterotopic ossifications are not always due to genetic abnormalities: other causes include trauma (as in myositis ossificans) and neurological disorders [17]. An unusual case of exuberant ossifications about multiple fracture sites was reported in a 33year-old man in whom the only potential risk factor was prolonged
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inhalation during the accident responsible for the fractures of high concentrations of an aerosol propellant (1,1-difluoroethane [DFE]) containing fluoride (C2 H4 F2 ) [18]. Spinal hyperostosis resembling DISH has been reported after long-term exposure to bexarotene [19], an anticancer agent used to treat breast cancer, lung cancer, and Kaposi’s sarcoma and capable of inducing amyloid deposit regression in murine models. Bexarotene activates the -retinoid receptor, and its ability to induce ossifications probably involves mechanisms similar to those triggered by retinoids. Long-term use of the retinoid etretinate to treat severe acne or erythrodermic psoriasis can induce hyperostosis along the joint capsules. These ossifications can cause joint stiffness, particularly at the hips, causing an inability to walk [20]. 3.5. Dickkopf-related protein-1 (DKK-1) In one study, serum levels of the osteoblast inhibitor DKK-1 were significantly lower in 37 patients with DISH than in 22 healthy age- and sex-matched controls (P < 0.0001). In addition, the lowest DKK-1 levels were associated with the greatest severity of spinal hyperostosis independently from age, sex, bone turnover markers, and bone mineral density [21]. However, another study failed to replicate this finding [22]. Rather than osteoblast dysfunction, abnormal differentiation of osteoblast precursors, most notably mesenchymous stem cells, may be central to the pathogenesis of DISH according to several recent studies (see below). 3.6. Genetic studies of patients with ossification of the posterior longitudinal ligament (OPLL): no convincing results to date OPLL frequently runs in families, with a pattern suggesting autosomal inheritance. A role for genetic co-factors is further supported by the high level of concordance in twins [23]. The gene or genes involved were first believed to be located between the Class II HLA genes and the collagen type 11 gene (COL11A2) [24]. Studies failed to confirm this possibility, and other collagen genes were therefore investigated. A study of seven COL6A1 polymorphisms in 97 Japanese and 96 Czech patients with OPLL versus 298 Japanese and 96 Czech controls showed overrepresentation of an intron polymorphism in the Japanese patients but not in the Czech patients. This finding may therefore be ascribable to chance, although abnormalities in COL6A1 are believed to promote the development of OPLL [25]. The most comprehensive study to date evaluated 109 polymorphisms of 35 candidate genes in 711 patients with OPLL and 896 controls [26]. The results failed to confirm any of the previously suspected associations (COL11A2, nucleotide pyrophosphatase gene [NPPS], and transforming growth factor 1 gene [TGFB1]). The only significant finding was a correlation between OPLL and a TGFB3 intron polymorphism (P = 0.00040) [26]. A role in OPLL is suspected for the vitamin D receptor gene and for genes encoding various cytokines and growth factors, chiefly the bone morphogenetic proteins (BMPs), but awaits confirmation [27]. The discrepancies across study results may be ascribable to the heterogeneity of OPLL, as strongly suggested by the fairly large number of animal models of OPLL. Thus, the identification of one or more susceptibility genes for OPLL may not be relevant to all forms of DISH, as DISH may also be a heterogeneous disease. In addition, whereas a fibroblast growth factor-1 (FGF-1) receptor polymorphism is associated with OPLL, a polymorphism in the FGF2 gene seems associated with DISH and another FGF2 polymorphism with ossification of the ligamentum flavum [28]. Nevertheless, a continuum probably exists between OPLL and some forms of DISH, as obesity and hyperinsulinism are risk factors for both conditions [27].
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3.7. Links between diffuse idiopathic skeletal hyperostosis and growth hormone Elevated serum levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) have been reported in patients with DISH compared to controls [29]. These elevated levels were not related to body mass index (BMI) [30] or presence of diabetes [31]. Only the GH levels correlated with joint and muscle pain and with stiffness [29]. GH elevations of similar magnitude were found in patients with rheumatoid arthritis, osteoarthritis, fibromyalgia, and joint laxity. Therefore, GH is probably not a major pathogenic factor in DISH. 3.8. Role for metabolic syndrome in the pathogenesis of diffuse idiopathic skeletal hyperostosis Strong associations were reported many years ago between the development of DISH and diabetes, familial diabetes, or hypertension. These associations have been confirmed in a few case-control studies in which the controls were healthy individuals or patients with osteoarthritis [32]. Hyperostosis seems more closely associated with type II than with type I diabetes [33]. DISH increases the cardiovascular risk independently from BMI and to a lesser degree. In a study of 47 patients with DISH matched to 48 controls, the 10-year risk of developing cardiovascular disease was very significantly increased in the patients (P = 0.007), although the serum lipid profiles were similar in the two groups [34]. In the same study, the prevalence of metabolic syndrome, which correlated strongly with excessive body weight, was 3.81 times higher in the group with DISH. Studies of carbohydrate and lipid metabolism in non-diabetic patients with DISH failed to identify major abnormalities compared to controls: the non-esterified triglyceride level was slightly lower and the insulin index minimally decreased, but no differences were found for IGF-1, IGF-1 binding protein 3 (IGF-BP3), uric acid, or cholesterol [31]. It would therefore be of interest to investigate the potential pathogenic role in DISH for adipokines, since these molecules are not only associated with metabolic syndrome, but also affect bone differentiation. 3.9. Role for adipokines in the pathogenesis of diffuse idiopathic skeletal hyperostosis Leptin levels are increased in patients with OPLL [35] and correlate with the severity and extent of the ossifications [36]. In vitro leptin exposure of cells from the ossified ligaments does not increase alkaline phosphatase activity or collagen synthesis [35]. However, the leptin receptor is expressed in the longitudinal ligaments. Thus, in conjunction with other stimuli, leptin may contribute to the ossification process in DISH, for instance by stimulating mesenchymatous cells. Leptin and its receptor are expressed in the anulus, where the leptin levels increase with advancing age [37]. Whereas mesenchymatous cell differentiation to adipocytes was previously thought to be the main effect of leptin, osteoinducing potential was unexpectedly documented in a recent study [38]. In addition, leptin is released within osteophytes in patients with osteoarthritis [39]. Among the other adipokines, adiponectin also deserves investigation, since it promotes osteoblastic differentiation of mesenchymatous cells [40], which are found in abundance in the entheses. 3.10. Role for mesenchymatous cells in the pathogenesis of diffuse idiopathic skeletal hyperostosis A key role for mesenchymatous cells in entheseal physiology and pathology has been established in murine models of enthesopathy. Thus, the speed and quality of lesion repair were
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greater after mesenchymatous cell injection than after chondrocyte injection [41]. Other studies evaluated the optimal conditions for differentiation of marrow mesenchymatous cells to tenocytes, chondrocytes, or bone cells according to their position in the enthesis. The results showed that mesenchymatous cell differentiation toward a tendon or bone phenotype depended on the degree of tensile loading: higher tensile loads (chiefly > 70–90 Pa) promoted osteogenic differentiation. However, this differentiation is also strongly influenced by paracrine signals (including the collagen-1 or fibronectin concentration), at least in the absence of strong tensile loads. High fibronectin concentrations promote osteogenic differentiation, whereas high collagen-1 concentrations inhibit osteogenic differentiation and promote differentiation to tenocytes [42]. These signals seem to converge toward BMP-2 production and the Smad8 signaling pathway, which strongly inhibits differentiation to osteoblasts [43] and promotes the development of tendon tissue within the enthesis [44]. Recent studies established that the abnormal bone production responsible for osteophyte formation was associated with the presence within osteophytes of mesenchymatous cells receiving abnormal signals from the adjacent cartilage and/or bone (excessive tensile loading and biological signals). Human osteophytes have been found to contain cells exhibiting a mesenchymatous cell phenotype (CD90+, CD105+, CD73+) and probably originating in the periosteum. These cells exhibit greater proliferative potential than do the other osteoblastic precursors such as marrow mesenchymatous cells [45]. They age more slowly and express larger amounts of BMP-2 compared to their marrow counterparts [46]. Proliferation of these periosteal mesenchymatous cells starts very early in murine models of experimental destructive arthritis (on day 3) and is not inhibited by blocking TNF or the RANK-RANKL pathway [47]. In all likelihood, these periosteal cells are at the origin of the abnormal ossifications in DISH. In rabbits, mesenchymatous cell injection into the intervertebral disks (after incision to induce degenerative changes) resulted in the development of large anterolateral osteophytes. The injected cells were identifiable within the osteophytes, suggesting a role in the abnormal bone formation. In-depth studies of cell migration outside the disks rare needed, and their results will determine whether intradiscal injections of autologous mesenchymal cells can be considered a potential treatment for human degenerative disk disease [48]. In humans, mesenchymatous cells have been identified in intervertebral disks in individuals aged 35 to 70 years [49], chiefly in a peripheral location. The main niche for progenitor mesenchymatous cells may be the junction of the anulus, vertebral ligaments, and endplate perichondrium [50]. From this site, the cells migrate to the nucleus and anulus [51] and may then travel to the tissues surrounding the disk. This topographic distribution is similar to that seen in the periosteum, the source of the mesenchymatous cells found in osteophytes [47]. In one of the murine models of OPLL, the nucleus cells first release excessive amounts of mucopolysaccharides, after which a tear occurs in the annulus; then, other cell types proliferate in the anulus and subsequently invade the posterior longitudinal ligament, where they induce hypervascularization and, above all, metaplasia to osteoblasts of the mesenchymatous cells already present within the ligaments [52]. Anterolateral disk tears may not constitute a prerequisite to the development of hyperostosis, however: mesenchymatous stem cells identified within the ligamentum flavum may be capable of differentiation to adipocytes, chondrocytes, or osteoblasts [53]; and mesenchymatous cells have been identified in various vertebral ligaments in eight Japanese patients undergoing surgery for lumbar spinal stenosis or OPLL. These cells were associated with the collagen matrix or small-vessel pericytes within the ligaments and were capable of in vitro differentiation to adipocytes, chondrocytes and, above all, bone cells
[54]. Taken in concert, these findings suggest that mesenchymatous cells at the periphery of the intervertebral disks and/or within the vertebral ligaments may play a central role in the pathogenesis of DISH. 3.11. Possible means of preventing mesenchymatous cell differentiation to osteoblasts The proliferation of spinal mesenchymatous cells and their transformation to fibroblasts, myoblasts, or osteoblasts under the influence of TGF-, which inhibits their differentiation to adipocytes, can be blocked by the TGF- inhibitor trichostatin A [53]. Trichostatin A might therefore hold promise for the treatment of lumbar spinal stenosis and some forms of DISH. However, the many other factors involved in mesenchymatous stem cell differentiation also hold potential s treatment targets. They include growth factors; hormones such as 1,25-dihydroxyvitamine D2 + D3, parathyroid hormone, and insulin; retinoids; and various BMPs including BMP-2 [55]. Other suggested treatments for DISH are BMP inhibitors (e.g. Noggin), BMP receptors [2], and nuclear agonists of the retinoic acid gamma-receptor [56]. In addition, as mentioned above, adipokines such as leptin might constitute treatment targets in both DISH and SpAs, since IL-17 increases the production of leptin by human marrow mesenchymatous cells [57]. 4. Conclusion Although the risk of severe upper airway and neurological complications associated with DISH is sufficient reason to investigate the pathogenesis of this condition [2], improved knowledge of DISH would probably lead to novel hypotheses regarding the mechanisms of the entheseal lesions seen in SpAs. Recent evidence suggests that some CD4-CD8- T-cells that strongly express the IL23 receptor are characterized by highly selective homing to the eye, aortic arch, and entheses [58]. Research into interactions between entheseal mesenchymatous cells and this T-cell subset might produce valuable insights, given the immunoregulating properties of mesenchymatous cells and recent evidence of a role for these cells in the ossification process in DISH. It would be unfortunate to confine studies into the pathogenesis of ankylosis in SpAs to osteoblasts and bone turnover markers, particularly as this line of research has so far failed to produce compelling results [2,59]. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Claudepierre P, Wendling D, Breban M, et al. Ankylosing spondylitis, spondyloarthropathy, spondyloarthritis, or spondylarthritis: what’s in a name? Joint Bone Spine 2012;79:534–5. [2] Mazières B. Diffuse idiopathic skeletal hyperostosis (Forestier-Rotes-Querol disease): what’s new? Joint Bone Spine 2013, doi:10.1016/j.jbspin.2013.02.011. [3] Wendling D, Prati C, Claudepierre P, et al. Non-radiographic spondyloarthritis: a theoretical concept or a real entity? Joint Bone Spine 2012;79:531–3. [4] Braem K, Deroose CM, Luyten FP, et al. Inhibition of inflammation but not ankylosis by glucocorticoids in mice: further evidence for the entheseal stress hypothesis. Arthritis Res Ther 2012;14:R59, doi:10.1186/ar3772. [5] Baraliakos X, Listing J, Buschmann J, et al. A comparison of new bone formation in patients with ankylosing spondylitis and patients with diffuse idiopathic skeletal hyperostosis: a retrospective cohort study over six years. Arthritis Rheum 2012;64:1127–33. [6] Ono M, Russell WJ, Kudo S, et al. Ossification of the thoracic posterior longitudinal ligament in a fixed population. Radiological and neurological manifestations. Radiology 1982;143:469–74. [7] Corman G, Jawad AS, Chikanza I. A family with diffuse idiopathic skeletal hyperostosis. Ann Rheum Dis 2005;64:1794–5.
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