State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Yunnan Key Laboratory of Stomatology, Kunming, China.
Int J Oral Sci. 2022 Jul 19;14(1):37. doi: 10.1038/s41368-022-00189-x.
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.
甲状旁腺激素相关肽（PTHrP）改善骨髓微环境以激活骨重塑，但 TMJ-OA 中 PTHrP 和转化生长因子-β（TGFβ）信号的协调调节仍不完全清楚。我们使用紊乱咬合建立了可重现 TMJ-OA 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，模型动物在紊乱咬合后髁突纤维软骨退化。间歇性给予 PTHrP（iPTH）的 TMJ-OA 模型动物，髁突软骨退化明显减少。Micro-CT、组织形态计量学和 Western Blot 分析显示，iPTH 促进 TMJ-OA 模型动物髁突下骨形成。此外，iPTH 增加了软骨下骨髓腔中骨钙素（OCN）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，这表明软骨下骨体积的增加主要是由于 iPTH 介导的髁突软骨下骨的骨形成能力增加。在体外，PTHrP 处理增加了髁突软骨下骨髓间充质干细胞（SMSC）成骨分化潜能，并上调了成骨关键调节因子的基因和蛋白表达。此外，我们发现 PTHrP-PTH1R 信号在成骨分化过程中抑制 TGFβ 信号。总之，这些数据表明，iPTH 通过增强软骨下骨中的成骨分化和抑制异常活跃的 TGFβ 信号来改善 OA 病变。这些发现表明，针对 TGFβ 信号通路的 PTHrP 可能是预防和治疗 TMJ-OA 的有效生物试剂。
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