Overexpressed TGF-β in Subchondral Bone Leads to Mandibular Condyle Degradation

Abstract

Emerging evidence has implied that subchondral bone plays an important role during osteoarthritis (OA) pathology. This study was undertaken to investigate whether abnormalities of the condylar subchondral bone lead to temporomandibular joint (TMJ) OA. We used an osteoblast-specific mutant TGF-β1 transgenic mouse, the CED mouse, in which high levels of active TGF-β1 occur in bone marrow, leading to abnormal bone remodeling. Subchondral bone changes in the mandibular condyles were investigated by micro-CT, and alterations in TMJ condyles were confirmed by histopathological and immunohistochemical analysis. Abnormalities in the condylar subchondral bone, characterized as fluctuant bone mineral density and microstructure and increased but uncoupled activity of osteoclasts and osteoblasts, were apparent in the 1- and 4-month CED mouse groups, while obvious cartilage degradation, in the form of cell-free regions and proteoglycan loss, was observed in the 4-month CED group. In addition, increased numbers of apoptotic chondrocytes and MMP9- and VEGF-positive chondrocytes were observed in the condylar cartilage in the 4-month CED group, but not in the 1-month CED group, compared with their respective age-matched controls. This study demonstrated that progressive degradation of mandibular condylar cartilage could be induced by the abnormal remodeling of the underlying subchondral bone during TMJOA progression.

Systemic administration of strontium or NBD peptide ameliorates early stage cartilage degradation of mouse mandibular condyles

“…In contrast, systemic administration of either strontium or NBD peptide induces no significant changes in non-UAC control condylar cartilage, and slightly increases the values of BV/TV and opg/rankl mRNA ratio in the subchondral bone. These findings are supported by the recent finding that abnormal remodeling of subchondral bone caused by activation of TGF-β signaling leads to OA-like pathological changes in cartilage of both knee and TMJs 32,33 , and inhibition of the TGF-β signaling could largely attenuate cartilage degeneration 32 . What deserves to be mentioned is that there were indeed profound cell losses in the fibrous layer, as well as in the proliferative layer of the articular cartilage in UAC groups.…”

Conditional removal of the canonical TGF-β1 signaling delays condylar cartilage degeneration induced by a partial discectomy in mice

“…We also did not observe the fibrillation in Tgfbr2 -deficient mice at 12 weeks after the partial discectomy. In line of the observation from this study, another independent research group reports that the increase in the expression of Tgf-β1 in the subchondral bone of TMJ in mice causes early onset condylar cartilage degeneration [20]. Based on these results, we conclude that inhibiting activity of TGF-β1 signaling in mature condylar cartilages can, in fact, protect the cartilages from being degraded.…”

Elevated marrow inflammatory cells and osteoclasts in subchondral osteosclerosis in human knee osteoarthritis

“…These findings are in line with our data showing increased osteoclast numbers in regions with subchondral osteosclerosis in advanced knee OA. Further evidence for uncoupled bone remodeling as underlying mechanism for OA progression has been recently demonstrated in experimental OA models . In these models, altered mechanical loading induced subchondral bone resorption followed by enhanced recruitment of osteoprogenitors and formation of osteoid islets in marrow spaces.…”

“…Molecular changes to human subchondral osteoblasts, including elevated expression of alkaline phosphatase and transforming growth factor‐beta1 (TGF‐β1) and blunted matrix mineralization in vitro, have been implied to be involved the onset and/or progression of OA . Recent investigations in experimental OA and osteoblast‐specific mutant TGF‐β1 transgenic mice have shown that spatiotemporal uncoupling of osteoclastic bone resorption and TGF‐β1‐induced recruitment of mesenchymal stem cells in the subchondral marrow compartment leads to aberrant bone formation and development of OA . Compositional changes of the subchondral marrow compartment in human OA have been frequently observed using magnetic resonance imaging (MRI) and these bone marrow lesions are a prognostic factor for OA progression and correlate spatially with sites of cartilage degeneration …”