PTH-related peptide (PTHrP) improves the bone marrow micro-environment to activate the bone-remodelling, but the coordinated regulation of PTHrP and transforming growth factor-β (TGFβ) signalling in TMJ-OA remains incompletely understood. We used disordered occlusion to establish model animals that recapitulate the ordinary clinical aetiology of TMJ-OA. Immunohistochemical and histological analyses revealed condylar fibrocartilage degeneration in model animals following disordered occlusion. TMJ-OA model animals administered intermittent PTHrP (iPTH) exhibited significantly decreased condylar cartilage degeneration. Micro-CT, histomorphometry, and Western Blot analyses disclosed that iPTH promoted subchondral bone formation in the TMJ-OA model animals. In addition, iPTH increased the number of osterix (OSX)-positive cells and osteocalcin (OCN)-positive cells in the subchondral bone marrow cavity. However, the number of osteoclasts was also increased by iPTH, indicating that subchondral bone volume increase was mainly due to the iPTH-mediated increase in the bone-formation ability of condylar subchondral bone. In vitro, PTHrP treatment increased condylar subchondral bone marrow-derived mesenchymal stem cell (SMSC) osteoblastic differentiation potential and upregulated the gene and protein expression of key regulators of osteogenesis. Furthermore, we found that PTHrP-PTH1R signalling inhibits TGFβ signalling during osteoblastic differentiation. Collectively, these data suggested that iPTH improves OA lesions by enhancing osteoblastic differentiation in subchondral bone and suppressing aberrant active TGFβ signalling. These findings indicated that PTHrP, which targets the TGFβ signalling pathway, may be an effective biological reagent to prevent and treat TMJ-OA in the clinic.

PTH 相关肽 (PTHrP) 改善骨髓微环境以激活骨重塑，但 PTHrP 和 TMJ-OA 中的转化生长因子-β (TGFβ) 信号传导的协调调节仍不完全清楚。我们使用无序闭塞来建立能够概括 TMJ-OA 的普通临床病因的模型动物。免疫组织化学和组织学分析显示模型动物在无序闭塞后发生髁突纤维软骨退化。给予间歇性 PTHrP (iPTH) 的 TMJ-OA 模型动物表现出显着减少的髁软骨退化。Micro-CT、组织形态计量学和蛋白质印迹分析表明，iPTH 促进了 TMJ-OA 模型动物的软骨下骨形成。此外，iPTH 增加了软骨下骨髓腔中 osterix (OSX) 阳性细胞和骨钙素 (OCN) 阳性细胞的数量。然而，iPTH 也增加了破骨细胞的数量，表明软骨下骨体积增加主要是由于 iPTH 介导的髁突软骨下骨成骨能力的增加。在体外，PTHrP 治疗增加了髁突软骨下骨髓来源的间充质干细胞 (SMSC) 成骨细胞分化潜能，并上调了成骨关键调节因子的基因和蛋白质表达。此外，我们发现 PTHrP-PTH1R 信号在成骨细胞分化过程中抑制 TGFβ 信号。集体，这些数据表明，iPTH 通过增强软骨下骨中的成骨细胞分化和抑制异常活跃的 TGFβ 信号传导来改善 OA 病变。这些发现表明，靶向 TGFβ 信号通路的 PTHrP 可能是临床上预防和治疗 TMJ-OA 的有效生物试剂。