异常的软骨下成骨代谢改变 Na1.8 以用于骨关节炎。
Aberrant subchondral osteoblastic metabolism modifies Na1.8 for osteoarthritis.
机构信息
Departments of Orthopaedic Surgery and Biomedical Engineering and Institute of Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, United States.
Department of Orthopaedic Surgery, Xiangya Hospital, Central South University, Changsha, China.
出版信息
Elife. 2020 May 22;9:e57656. doi: 10.7554/eLife.57656.
Pain is the most prominent symptom of osteoarthritis (OA) progression. However, the relationship between pain and OA progression remains largely unknown. Here we report osteoblast secret prostaglandin E2 (PGE2) during aberrant subchondral bone remodeling induces pain and OA progression in mice. Specific deletion of the major PGE2 producing enzyme cyclooxygenase 2 (COX2) in osteoblasts or PGE2 receptor EP4 in peripheral nerve markedly ameliorates OA symptoms. Mechanistically, PGE2 sensitizes dorsal root ganglia (DRG) neurons by modifying the voltage-gated sodium channel Na1.8, evidenced by that genetically or pharmacologically inhibiting Na1.8 in DRG neurons can substantially attenuate OA. Moreover, drugs targeting aberrant subchondral bone remodeling also attenuates OA through rebalancing PGE2 production and Na1.8 modification. Thus, aberrant subchondral remodeling induced Na1.8 neuronal modification is an important player in OA and is a potential therapeutic target in multiple skeletal degenerative diseases.
疼痛是骨关节炎（OA）进展的最突出症状。然而，疼痛与 OA 进展之间的关系在很大程度上仍然未知。在这里，我们报告了成骨细胞在异常的软骨下骨重塑过程中分泌的前列腺素 E2（PGE2）会在小鼠中引起疼痛和 OA 进展。成骨细胞中环氧合酶 2（COX2）或外周神经中 PGE2 受体 EP4 的特异性缺失显著改善了 OA 症状。在机制上，PGE2 通过改变电压门控钠离子通道 Na1.8 使背根神经节（DRG）神经元敏感，这一点通过在 DRG 神经元中遗传或药理学抑制 Na1.8 得到证实，OA 可以得到显著缓解。此外，针对异常软骨下骨重塑的药物也通过重新平衡 PGE2 的产生和 Na1.8 的修饰来减轻 OA。因此，异常的软骨下重塑诱导的 Na1.8 神经元修饰是 OA 的一个重要参与者，也是多种骨骼退行性疾病的潜在治疗靶点。
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