Objective. Osteocytes are considered to be sensors of bone damage and regulators of bone mass by specifically expressing sclerostin, an inhibitor of bone formation. The contribution of osteocytes in regulating local bone remodeling in arthritis is unknown. The aim of this study was to investigate the role of osteocytes as contributors to bone remodeling in ankylosing spondylitis (AS).Methods. Sclerostin expression and osteocyte death were assessed by immunohistochemistry in joints derived from patients with AS, patients with rheumatoid arthritis (RA), and patients with osteoarthritis (OA), as well as from control subjects. In addition, the serum level of sclerostin was assessed by enzyme-linked immunosorbent assay in healthy subjects and patients with AS; this assessment included the longitudinal correlation of sclerostin serum levels and radiographic progression in the spine of patients with AS.Results. Sclerostin expression was confined exclusively to osteocytes. Whereas the majority of osteocytes in healthy individuals and patients with RA were sclerostin positive, expression was significantly reduced in patients with OA and was virtually absent in patients with AS. Moreover, serum levels of sclerostin were significantly lower in patients with AS than in healthy individuals. Importantly, low serum sclerostin levels in patients with AS were significantly associated with the formation of new syndesmophytes (P ‫؍‬ 0.007).Conclusion. Sclerostin expression is impaired in patients with AS, suggesting a specific alteration of osteocyte function in this disease. A low serum level of sclerostin in the setting of AS is linked to increased structural damage, emphasizing the role of sclerostin in the suppression of bone formation.Ankylosing spondylitis (AS) is an inflammatory disease that predominantly affects axial joints and intervertebral spaces. AS is characterized by tight interplay between chronic inflammation and bone formation (1), which is only partly understood. Local inflammation appears to be crucial for bony proliferations along periosteal and entheseal sites (1). Inflammatory lesions are typically located in the subchondral bone marrow (2-4) and are preferentially seen at sites that later develop bony proliferations and ankylosis (3,4), suggesting a link between inflammation and bone formation.These observations, which suggest a functional link between inflammatory lesions inside the cortical bone barrier and bony proliferations outside this barrier, indicate that there is certain kind of "communication"Drs.

Background Osteophyte formation is a common phenomenon in arthritis. Bone formation by endochondral ossifi cation is considered a key pathophysiological process in the formation of osteophytes. Objective To examine the hypothesis that inhibition of smoothened (Smo), a key component of the hedgehog pathway inhibits osteophyte formation as the hedgehog pathway mediates endochondral ossifi cation. Methods Arthritis was induced in 8-week-old C57/BL6 mice by serum transfer (K/BxN model). Mice were then treated by daily administration of either vehicle or LDE223, a specifi c small molecule inhibitor for Smo, over 2 weeks starting at the onset of disease. Clinical course of arthritis, histological and molecular changes of bone in the affected joints as well as systemic bone changes were assessed. Results Serum transfer-induced arthritis led to severe osteophyte formation within 2 weeks of onset. Blockade of Smo inhibited hedgehog signalling in vivo and also signifi cantly inhibited osteophyte formation, whereas the clinical and histopathological signs of arthritis were not affected. Also, systemic bone mass did not change. Smo inhibitor particularly blocked the formation of hypertrophic chondrocytes and collagen type X expression. Conclusions The data indicate that blockade of hedgehog signalling by targeting Smo specifi cally inhibits osteophyte formation in arthritis without affecting infl ammation and without eliciting bone destruction at the local and systemic level. Blockade of Smo may thus be considered as a strategy to specifi cally infl uence the periosteal bone response in arthritis associated with bone apposition.

Objective To test whether the tyrosine kinase Tyro3 affects arthritis. Tyro3, the ligand of growth arrest-specific protein 6 (GAS6) is a receptor tyrosine kinase involved in cell survival. Tyro3 and GAS6 are expressed in the arthritic synovium, and in vitro studies have shown their role in osteoclast differentiation. Methods Bone was assessed by micro CT and histomorphometry in Tyro3-deficient (Tyro3) and wild-type mice. Arthritis was induced in both genotypes, and Gas6 level was measured by ELISA. Synovitis, synovial hyperplasia, bone erosion, osteoclast activation and osteoclast gene expression were assessed by histomorphometry and reverse transcriptase-PCR, respectively. In vitro osteoclast differentiation assays were performed in Tyro3−/− and wild-type mice. Furthermore, effects of Tyro3 and GAS6 on human synovial fibroblast proliferation and osteoclastogenesis were assessed in human cells. Results Tyro3−/− mice had significantly higher bone mass than wild-type littermates. Induction of arthritis increased GAS6 serum levels. Arthritic Tyro3 −/− mice showed less synovial hyperplasia, osteoclast numbers and bone damage compared with controls. In vivo expression of osteoclast-associated receptor and receptor activator of nuclear factor-κB and in vitro osteoclastogenesis were impaired in Tyro3 −/− mice. GAS6 also induced synovial fibroblast proliferation and osteoclast differentiation in human cells in Tyro3-dependent manner. Conclusions These findings indicate that Tyro3 is a critical signal for synovial hyperplasia, osteoclast differentiation and bone erosion during arthritis. GAS6 and Tyro3 therefore constitute therapeutic targets to inhibit synovial hyperplasia and associated bone erosion.

Current clinical evidences suggest that circulating Adipokines such as Adiponectin can influence the ratio of orthodontic tooth movement. We aimed to investigate the effect that Adiponectin has on cementoblasts (OCCM-30) and on the intracellular signaling molecules of Mitogen-activated protein kinase (MAPK). We demonstrated that OCCM-30 cells express AdipoR1 and AdipoR2. Alizarin Red S staining revealed that Adiponectin increases mineralized nodule formation and quantitative AP activity in a dose-dependent manner. Adiponectin up-regulates the mRNA levels of AP, BSP, OCN, OPG, Runx-2 as well as F-Spondin. Adiponectin also increases the migration and proliferation of OCCM-30 cells. Moreover, Adiponectin induces a transient activation of JNK, P38, ERK1/2 and promotes the phosphorylation of STAT1 and STAT3. The activation of Adiponectin-mediated migration and proliferation was attenuated after pharmacological inhibition of P38, ERK1/2 and JNK in different degrees, whereas mineralization was facilitated by MAPK inhibition in varying degrees. Based on our results, Adiponectin favorably affect OCCM-30 cell migration, proliferation as well as cementogenesis. One of the underlying mechanisms is the activation of MAPK signaling pathway.

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