Abstract
As the initial part in the development of osteoarthritis (OA), subchondral bone sclerosis has been considered to be initiated by excess mechanical loading and proven to be correlated to other pathological changes. Sclerostin, which is an essential mechanical stress response protein, is encoded by the SOST gene. It is expressed in osteocytes and mature chondrocytes and has been proven to be closely correlated to OA. However, the relationship and mechanism between the SOST gene and the development of OA remain unclear. The aim of the present study was to investigate the role of the SOST gene in OA pathogenesis in the subchondral bone. A knee anterior cruciate ligament transection (ACLT) mouse osteoarthritis (OA) model on SOST-knockout (SOST KO) and wild-type (WT) mice was established. The pathogenic and phenotypic changes in the subchondral bone were investigated by histology, micro-CT, immunohistochemistry, TRAP staining, Masson staining, and Toluidine blue staining. It was found that sclerostin expression decreased in both the calcified cartilage and mineralized subchondral structures during the development of OA. Joint instability induced a severe cartilage degradation phenotype, with higher OARSI scores in SOST KO mice, when compared to WT mice. SOST KO mice with OA exhibited a higher BMD and BV/TV ratio, as well as a higher rate of bone remodeling and TRAP-positive cell number, when compared to the WT counterparts, but the difference was not significant between the sham-operation groups. It was concluded that loss of sclerostin aggravates knee OA in mice by promoting subchondral bone sclerosis and increasing catabolic activity of cartilage.
Highlights
Osteoarthritis (OA) is a degenerative joint disease, and the main pathological features are cartilage degradation, subchondral bone sclerosis, and osteophyte. e pathophysiological mechanism of the cartilage degradation of OA has been widely considered to be closely correlated to bone under mechanical loading [1]
SOST/sclerostin is a canonical Wnt antagonist primarily synthesized by mature osteocytes and hypertrophic chondrocytes and functions as an osteogenesis inhibitor [4]
SOST gene mutation in human causes Van Buchem disease or sclerosteosis, which are both characterized as hyperostosis [9, 10]
Summary
Osteoarthritis (OA) is a degenerative joint disease, and the main pathological features are cartilage degradation, subchondral bone sclerosis, and osteophyte. e pathophysiological mechanism of the cartilage degradation of OA has been widely considered to be closely correlated to bone under mechanical loading [1]. SOST/sclerostin is a canonical Wnt antagonist primarily synthesized by mature osteocytes and hypertrophic chondrocytes and functions as an osteogenesis inhibitor [4] It has been considered as an important mediator of mechanical loading-induced new bone formation [4,5,6,7,8]. E pathogenesis of OA is closely correlated to joint loading, and studies have shown that SOST is elevated in the cartilage but decreased in the subchondral bone in OA, suggesting opposing effects through the promotion of disease-associated subchondral bone sclerosis, while inhibiting the degradation of cartilage [12]. It was hypothesized that sclerostin plays a protective role in the development of OA through the negative control of subchondral bone osteogenesis and plays an anabolic role in cartilage, which is enhanced through the over loading of the joint at the early stage of the disease. A knee instability model was constructed to induce OA in wild-type (WT) and SOST gene knockout (SOST KO) mice and found a severer OA phenotype in SOST KO mice, in which bone formation in the subchondral unit increased only when stress was loaded, indicating the stress-dependent protective role of sclerosis on the early stage of OA
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