Department of Orthopaedic Surgery, Institute of Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, United States.
Department of Orthopaedics, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
Elife. 2021 Mar 1;10:e66532. doi: 10.7554/eLife.66532.
Osteoarthritis, a highly prevalent degenerative joint disorder, is characterized by joint pain and disability. Available treatments fail to modify osteoarthritis progression and decrease joint pain effectively. Here, we show that intermittent parathyroid hormone (iPTH) attenuates osteoarthritis pain by inhibiting subchondral sensory innervation, subchondral bone deterioration, and articular cartilage degeneration in a destabilized medial meniscus (DMM) mouse model. We found that subchondral sensory innervation for osteoarthritis pain was significantly decreased in PTH-treated DMM mice compared with vehicle-treated DMM mice. In parallel, deterioration of subchondral bone microarchitecture in DMM mice was attenuated by iPTH treatment. Increased level of prostaglandin E2 in subchondral bone of DMM mice was reduced by iPTH treatment. Furthermore, uncoupled subchondral bone remodeling caused by increased transforming growth factor β signaling was regulated by PTH-induced endocytosis of the PTH type 1 receptor-transforming growth factor β type 2 receptor complex. Notably, iPTH improved subchondral bone microarchitecture and decreased level of prostaglandin E2 and sensory innervation of subchondral bone in DMM mice by acting specifically through PTH type 1 receptor in Nestin mesenchymal stromal cells. Thus, iPTH could be a potential disease-modifying therapy for osteoarthritis.
骨关节炎是一种高发的退行性关节疾病，其特征为关节疼痛和功能障碍。现有的治疗方法无法有效减缓骨关节炎的进展和减轻关节疼痛。在这里，我们发现间歇性甲状旁腺素（iPTH）通过抑制软骨下感觉神经支配、软骨下骨恶化和不稳定内侧半月板（DMM）小鼠模型中的关节软骨退化，从而减轻骨关节炎疼痛。我们发现，与 vehicle 处理的 DMM 小鼠相比，PTH 处理的 DMM 小鼠的软骨下感觉神经支配对于骨关节炎疼痛明显减少。同时，iPTH 治疗可减轻 DMM 小鼠软骨下骨微结构的恶化。iPTH 治疗可降低 DMM 小鼠软骨下骨中前列腺素 E2 的水平。此外，通过 PTH 诱导的 PTH 型 1 受体-转化生长因子β型 2 受体复合物的内吞作用，调节了由转化生长因子β信号增加引起的未偶联的软骨下骨重塑。值得注意的是，iPTH 通过在巢蛋白间充质基质细胞中特异性作用于 PTH 型 1 受体，改善了 DMM 小鼠的软骨下骨微结构，降低了前列腺素 E2 的水平，并减少了软骨下骨的感觉神经支配。因此，iPTH 可能是一种潜在的骨关节炎治疗方法。
