Bone Abstracts

The re-initiation of developmental processes in osteoarthritis (OA) has emerged with similarities to endochondral ossification; responsible for long bone development. We aimed to establish the role of the Wnt inhibitor, sclerostin in endochondral ossification, and its relationship with MEPE, a calcification inhibitor with potential downstream functions. Knee joints from male Str/ort (spontaneous OA) and age-matched CBA control mice were analysed at 8, 18, and 40+ weeks of age (before, early and late OA). Subchondral bone (SB)-thickness was measured by microCT. Joints were scored for OA hallmarks and related to immunohistochemical (IHC) sclerostin/MEPE expression. We have previously established MEPE as an inhibitor of endochondral ossification however the role of sclerostin is unknown. Thus embryonic and postnatal growth-plates were analysed for sclerostin by IHC. Chondrogenic ATDC5 cells were cultured in mineralizing conditions and examined for sclerostin protein by western blotting. Our results reveal enhanced sclerostin expression at the osteochondral interface, and enhanced MEPE expression in the articular cartilage (AC) in unaffected regions of the Str/ort mouse joint. At advanced stages of OA, site-specific suppression of sclerostin and MEPE expression is observed in regions of SB-thickening (analysed by microCT scanning) and where AC integrity is compromised. Strong expression of sclerostin and MEPE are observed in ossified ligaments, menisci, and emerging osteophytes; all increased with disease severity. Osteophytes form through endochondral ossification thus we examined localisation of sclerostin during endochondral bone growth. Interestingly, sclerostin expression is observed in embryonic proliferating and calcifying hypertrophic chondrocytes, however this is lost in all postnatal chondrocytes. Our results also show increased sclerostin expression in ATDC5 cells, consistent with increasing calcification. Our data suggest sclerostin and MEPE are pivotal in restricting the endochondral processes observed in osteophyte formation and OA pathology. Further investigation into their underpinning mechanisms will identify whether their targeted delivery can protect against OA pathology.