Department of Orthopaedics, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China.
Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China.
Cells. 2022 Sep 5;11(17):2760. doi: 10.3390/cells11172760.
Aberrant subchondral bone architecture is a crucial driver of the pathological progression of osteoarthritis, coupled with increased sensory innervation. The sensory PGE2/EP4 pathway is involved in the regulation of bone mass accrual by the induction of differentiation of mesenchymal stromal cells. This study aimed to clarify whether the sensory PGE2/EP4 pathway induces aberrant structural alteration of subchondral bone in osteoarthritis. Destabilization of the medial meniscus (DMM) using a mouse model was combined with three approaches: the treatment of celecoxib, capsaicin, and sensory nerve-specific prostaglandin E2 receptor 4 (EP4)-knockout mice. Cartilage degeneration, subchondral bone architecture, PGE2 levels, distribution of sensory nerves, the number of osteoprogenitors, and pain-related behavior in DMM mice were assessed. Serum and tissue PGE2 levels and subchondral bone architecture in a human sample were measured. Increased PGE2 is closely related to subchondral bone's abnormal microstructure in humans and mice. Elevated PGE2 concentration in subchondral bone that is mainly derived from osteoblasts occurs in early-stage osteoarthritis, preceding articular cartilage degeneration in mice. The decreased PGE2 levels by the celecoxib or sensory denervation by capsaicin attenuate the aberrant alteration of subchondral bone architecture, joint degeneration, and pain. Selective EP4 receptor knockout of the sensory nerve attenuates the aberrant formation of subchondral bone and facilitates the prevention of cartilage degeneration in DMM mice. Excessive PGE2 in subchondral bone caused a pathological alteration to subchondral bone in osteoarthritis and maintaining the physiological level of PGE2 could potentially be used as an osteoarthritis treatment.
软骨下骨结构异常是骨关节炎病理进展的关键驱动因素，伴随着感觉神经支配的增加。感觉 PGE2/EP4 通路参与调节骨髓基质细胞的分化，从而促进骨量的积累。本研究旨在阐明感觉 PGE2/EP4 通路是否诱导骨关节炎软骨下骨的异常结构改变。使用小鼠模型对内侧半月板进行不稳定处理（DMM），并结合三种方法：塞来昔布治疗、辣椒素治疗和感觉神经特异性前列腺素 E2 受体 4（EP4）敲除小鼠。评估 DMM 小鼠的软骨退变、软骨下骨结构、PGE2 水平、感觉神经分布、成骨前体细胞数量和与疼痛相关的行为。测量了人类样本中的血清和组织 PGE2 水平以及软骨下骨结构。在人类和小鼠中，PGE2 的增加与软骨下骨的异常微观结构密切相关。在关节炎早期，即小鼠关节软骨退变之前，主要来源于成骨细胞的软骨下骨中 PGE2 浓度升高。塞来昔布降低 PGE2 水平或辣椒素感觉神经切断术降低了软骨下骨结构、关节退变和疼痛的异常改变。感觉神经的选择性 EP4 受体敲除减轻了 DMM 小鼠软骨下骨的异常形成，并促进了软骨退变的预防。软骨下骨中过量的 PGE2 导致骨关节炎软骨下骨的病理性改变，维持 PGE2 的生理水平可能可用于骨关节炎的治疗。
