This study shows that stigmasterol inhibits several pro-inflammatory and matrix degradation mediators typically involved in OA-induced cartilage degradation, at least in part through the inhibition of the NF-kappaB pathway. These promising results justify further ex vivo and in vivo investigations with stigmasterol.

These results demonstrate that SC OA subchondral osteoblasts could contribute to cartilage degradation by stimulating chondrocytes to produce more MMP and also by inhibiting AGG synthesis.

In co-culture, SC subchondral osteoblasts decrease SOX9, COL2, PTHrP and PTH-R gene expression by chondrocytes but increase that of OSF-1. These findings suggest that SC osteoblasts could initiate chondrocyte phenotype shift towards hypertrophic differentiation and subsequently further matrix mineralization.

Objective. To determine the phenotype of osteoblasts from the sclerotic zones of human osteoarthritic (OA) subchondral bone.Methods. Human osteoblasts were isolated from sclerotic or nonsclerotic areas of subchondral bone and cultured for 14 days in monolayer. The expression of 14 genes was investigated by real-time reverse transcriptionpolymerase chain reaction. The activities of alkaline phosphatase (AP) and transglutaminases (TGases) were quantified by enzymatic assays. C-terminal type I procollagen propeptide (CPI), interleukin-1␤ (IL-1␤), IL-6, IL-8, transforming growth factor ␤1 (TGF␤1), osteocalcin (OC), and osteopontin (OPN) were assayed in the culture medium by immunoassay.Results. Gene expression levels of matrix metalloproteinase 13, COL1A1 and COL1A2, OPN, tissuenonspecific AP, OC, vascular endothelial growth factor, ANKH, TGase 2, factor XIIIA, and dentin matrix protein 1 were significantly up-regulated in sclerotic osteoblasts compared with nonsclerotic osteoblasts. In contrast, parathyroid hormone receptor gene expression was depressed in sclerotic osteoblasts, but bone sialoprotein levels were unchanged. The activities of AP and TGases were increased in sclerotic osteoblasts, while matrix mineralization, revealed by alizarin red staining, was decreased. In parallel, protein synthesis of CPI, OC, OPN, IL-6, IL-8, and TGF␤1 was significantly higher in sclerotic osteoblasts than in nonsclerotic osteoblasts, while IL-1␤ production was similar in both groups.Conclusion. These findings contribute to a better understanding of the mechanisms involved in subchondral bone sclerosis and identify osteoblasts with an altered phenotype as a potential target for future OA therapies.Osteoarthritis (OA) is a common leading cause of disability in the elderly that is characterized by cartilage degradation, synovium and tendon inflammation, muscle weakness, osteophyte formation, and subchondral bone plate thickening (1). Although it is not yet clear whether it precedes (2-4) or occurs subsequently to cartilage damage (5-7), subchondral bone remodeling is an important feature in the pathophysiology of OA and is characterized by osteoid substance accumulation, decreased mineralization, and increased amounts of type I homotrimer (8). It is speculated that subchondral bone remodeling is linked to cartilage degradation, not only by modifying the mechanical properties of the subchondral bone (9) but also by releasing factors that may influence cartilage metabolism (10,11). Thus, the understanding of the mechanisms leading to bone sclerosis is of the utmost importance in the treatment of OA.Indeed, previous studies have demonstrated that some osteoblasts are phenotypically different and may produce increased levels of alkaline phosphatase (AP), osteocalcin (OC), transforming growth factor ␤1 (TGF␤1), insulin-like growth factor 1 (IGF-1), and urokinase plasminogen activator, while levels of IGF binding proteins 3, 4, and 5 are lower and plasminogen activator inhibitor 1 and interleukin-1␤ (IL-1␤) levels remain unchanged (12...

This work demonstrates that IL-6 is mechano-sensitive cytokine and probably a key factor in the biomechanical control of bone remodeling in OA.