Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA.
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Biomolecules. 2023 Oct 20;13(10):1553. doi: 10.3390/biom13101553.
Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 signaling, shutting down autophagy and blocking ER clearance, resulting in premature loss of chondrocytes that negatively impacts linear growth and causes early joint degeneration in MT-COMP mice and PSACH. Previously, we have shown that resveratrol treatment from birth to 20 weeks prevents joint degeneration and decreases the pathological processes in articular chondrocytes. Resveratrol's therapeutic mechanism of action in the mutant-COMP pathology was shown to act by primarily stimulating autophagy and reducing inflammation. Importantly, we demonstrated that MT-COMP mice experience pain consistent with PSACH joint pain. Here, we show, in the MT-COMP mouse, that resveratrol treatment must begin within 4 weeks to preserve joint health and reduce pain. Resveratrol treatment started at 6 or 8 weeks (to 20 weeks) was not effective in preventing joint degeneration. Collectively, our findings in MT-COMP mice show that there is a postnatal resveratrol treatment window wherein the inevitable mutant-COMP joint degeneration and pain can be prevented.
假性软骨发育不全症（PSACH）是一种严重的侏儒症，与早发性关节退化和终生关节疼痛有关，由软骨寡聚基质蛋白（COMP）的突变引起。使用 PSACH 的 MT-COMP 小鼠模型已经定义了突变型 COMP 病理学的机制，该模型具有常见的 D469del 突变。突变型 COMP 蛋白不能正确折叠，并且在软骨细胞的粗面内质网（rER）中保留，而不是被输出到细胞外基质（ECM），从而驱动内质网应激，刺激氧化应激和炎症，驱动自我维持的循环。CHOP（内质网应激信号蛋白）和 TNFα 炎症驱动 mTORC1 信号的高水平，关闭自噬并阻止内质网清除，导致软骨细胞过早丢失，这对线性生长产生负面影响，并导致 MT-COMP 小鼠和 PSACH 的早期关节退化。以前，我们已经表明，从出生到 20 周的白藜芦醇治疗可预防关节退化并减少关节软骨细胞中的病理过程。白藜芦醇在突变型 COMP 病理学中的治疗作用机制表明，主要通过刺激自噬和减少炎症起作用。重要的是，我们证明 MT-COMP 小鼠经历与 PSACH 关节疼痛一致的疼痛。在这里，我们在 MT-COMP 小鼠中表明，白藜芦醇治疗必须在 4 周内开始才能维持关节健康并减轻疼痛。从 6 周或 8 周（至 20 周）开始的白藜芦醇治疗在预防关节退化方面无效。总的来说，我们在 MT-COMP 小鼠中的发现表明，存在一个产后白藜芦醇治疗窗口，在此期间可以预防不可避免的突变型 COMP 关节退化和疼痛。
