Riggs Keegan C, Sankar Uma
Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA.
Immunometabolism (Cobham). 2023 Oct 16;5(4):e00031. doi: 10.1097/IN9.0000000000000031. eCollection 2023 Oct.
Post-traumatic osteoarthritis (PTOA) is a multifactorial disease of the cartilage, synovium, and subchondral bone resulting from direct joint trauma and altered joint mechanics after traumatic injury. There are no current disease-modifying therapies for PTOA, and early surgical interventions focused on stabilizing the joint do not halt disease progression. Chronic pain and functional disability negatively affect the quality of life and take an economic toll on affected patients. While multiple mechanisms are at play in disease progression, joint inflammation is a key contributor. Impact-induced mitochondrial dysfunction and cell death or altered joint mechanics after trauma culminate in inflammatory cytokine release from synoviocytes and chondrocytes, cartilage catabolism, suppression of cartilage anabolism, synovitis, and subchondral bone disease, highlighting the complexity of the disease. Current understanding of the cellular and molecular mechanisms underlying the disease pathology has allowed for the investigation of a variety of therapeutic strategies that target unique apoptotic and/or inflammatory processes in the joint. This review provides a concise overview of the inflammatory and apoptotic mechanisms underlying PTOA pathogenesis and identifies potential therapeutic targets to mitigate disease progression. We highlight Ca/calmodulin-dependent protein kinase kinase 2 (CaMKK2), a serine/threonine protein kinase that was recently identified to play a role in murine and human osteoarthritis pathogenesis by coordinating chondrocyte inflammatory responses and apoptosis. Given its additional effects in regulating macrophage inflammatory signaling and bone remodeling, CaMKK2 emerges as a promising disease-modifying therapeutic target against PTOA.
创伤后骨关节炎（PTOA）是一种由直接关节创伤和创伤性损伤后关节力学改变导致的软骨、滑膜和软骨下骨的多因素疾病。目前尚无针对PTOA的疾病改善疗法，早期旨在稳定关节的手术干预并不能阻止疾病进展。慢性疼痛和功能障碍会对生活质量产生负面影响，并给受影响的患者带来经济负担。虽然多种机制在疾病进展中起作用，但关节炎症是一个关键因素。撞击诱导的线粒体功能障碍和细胞死亡或创伤后关节力学改变最终导致滑膜细胞和软骨细胞释放炎性细胞因子、软骨分解代谢、软骨合成代谢受抑制、滑膜炎和软骨下骨疾病，凸显了该疾病的复杂性。目前对该疾病病理基础的细胞和分子机制的理解使得人们能够研究针对关节中独特凋亡和/或炎症过程的多种治疗策略。本综述简要概述了PTOA发病机制中的炎症和凋亡机制，并确定了减轻疾病进展的潜在治疗靶点。我们重点介绍了钙/钙调蛋白依赖性蛋白激酶激酶2（CaMKK2），这是一种丝氨酸/苏氨酸蛋白激酶，最近被发现通过协调软骨细胞炎症反应和凋亡在小鼠和人类骨关节炎发病机制中发挥作用。鉴于其在调节巨噬细胞炎症信号和骨重塑方面的额外作用，CaMKK2成为一种有前景的针对PTOA的疾病改善治疗靶点。
