Treatment of a mouse model of ankylosing spondylitis with exogenous sclerostin has no effect on disease progression

Abstract

BackgroundNo treatment to date is available which specifically targets bone formation in ankylosing spondylitis (AS). Several recent studies have shown that sclerostin (SOST), a Wnt inhibitor specific to osteocytes and chondrocytes, is down-regulated in AS patients. This suggests Wnt signalling may be upregulated, and application of exogenous recombinant SOST (rSOST) may inhibit Wnt signalling and slow pathological bone formation.MethodsThe proteoglycan-induced spondylitis (PGISp) mouse model in which we have previously demonstrated downregulated SOST expression, was used for this study. Mice were injected with 2.5ug rSOST/day for a period of 8 weeks following induction of disease. Axial skeleton disease development was assessed by histology and skeletal changes examined using DEXA.ResultsrSOST treatment had no effect on peripheral or axial disease development, bone density or disease severity. Injected rSOST was stable over 8 h and residual levels were evident 24 h after injection, resulting in a cumulative increase in SOST serum levels over the treatment time course. Immunohistochemical examination of SOST levels within the joints in non-rSOST treated PGISp mice showed a significant decrease in the percentage of positive osteocytes in the unaffected joints compared to the affected joints, while no difference was seen in rSOST treated mice. This suggests that rSOST treatment increases the number of SOST-positive osteocytes in unaffected joints but not affected joints, despite having no impact on the number of joints affected by disease.ConclusionsAlthough not disease-modifying, rSOST treatment did appear to regulate SOST levels in the joints suggesting biological activity. Further dose response studies are required and SOST may require modifications to improve its bone targeting ability in order to affect tissue formation to a meaningful level in this model.

Inflammation Intensity–Dependent Expression of Osteoinductive Wnt Proteins Is Critical for Ectopic New Bone Formation in Ankylosing Spondylitis

“…Previous studies have shown that some members are osteogenic. However, results have varied among studies due to differences in experimental conditions, cell types, stimulation methods and durations, and osteogenesis measurements . We screened all family members in the current culture system using different osteoprogenitor cell types to compare the osteogenic abilities of the Wnt proteins.…”

“…Four non‐transgenic models are most frequently used to study bone and joint pathology in rheumatic diseases: spontaneous arthritis in DBA/1 mice, CIA, collagen antibody–induced arthritis, and proteoglycan‐induced arthritis/PGIS. In all of these models, bone remodeling and new bone formation were found to be closely correlated to the inflammation process (). Of these models, osteophytes in the paws of DBA/1 mice and syndesmophytes leading to vertebral bony bridging in the PGIS model are most widely considered to be pathologic changes similar to new bone formation in the axial skeleton of patients with AS.…”

microRNA‐96 promotes osteoblast differentiation and bone formation in ankylosing spondylitis mice through activating the Wnt signaling pathway by binding to SOST

“…13 Meanwhile, sclerostin, a type of protein encoded by SOST, is expressed unambiguously in chondrocytes and osteocytes and serum SOST may function as an indicator for ossification progression and a diagnostic marker of AS at advanced stage. 14,15 It has been documented that SOST was poorly expressed in AS. 16,17 SOST has been proposed to be a modulator that restrains the Wnt signaling pathway in skeletal tissues.…”

“…16,17 SOST has been proposed to be a modulator that restrains the Wnt signaling pathway in skeletal tissues. 14 A predominant association of the Wnt signaling pathway has been implicated with tissue homeostasis and development through regulation of endogenous stem cells, and abnormal Wnt pathway is involved in cancer initiation and progression by affecting cancer stem cells. 18 The Wnt signaling pathway has been speculated that it impacts the bone marrow adipogenesis, homeostasis, and bone morphogenesis, as well as differentiation and activation of T cells in AS, which may provide useful insights for AS treatment.…”

Loss and gain of bone in spondyloarthritis: what drives these opposing clinical features?

“… 58 However, in a mouse model of AS, SOST was unable to prevent peripheral or axial disease development, or affect bone density or disease severity. 59 In humans, there are no reported genetic links from GWAS studies to suggest a role for the Wnt family members in SpA. So, although SOST levels have been suggested as a biomarker in SpA, there is considerable controversy in this area and changes in SOST and DKK1 appear to be consequential, rather than causative, of bone changes.…”