Pathophysiological Insights Into the Role of Osteoclasts in Osteoarthritis: Mechanisms, Therapeutic Targets, and Future Directions

Shuai Chen,1,2,* Yinqi Long,1,* Zijian Guo,1,2 Jingkai Di,1 Jiake Xu,3– 5 Chuan Xiang1 1Department of Orthopedics, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 2Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Department of Orthopedics, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 3Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People’s Republic of China; 4Shenzhen University of Advanced Technology, Shenzhen, People’s Republic of China; 5School of Biomedical Sciences, the University of Western Australia, Perth, Australia*These authors contributed equally to this workCorrespondence: Jiake Xu; Chuan Xiang, Email [email protected]; [email protected]: Osteoarthritis (OA) is the most prevalent musculoskeletal issue. In the absence of effective pharmacological interventions, advanced stages of this disease frequently necessitate joint replacement surgery, thereby imposing a substantial socioeconomic burden. An increasing number of studies suggest that subchondral bone osteoclasts are crucial for the onset of arthritis, even before the formation of cartilage lesions. Osteoclasts are the only type of cells responsible for bone resorption and are integral to the etiology of OA. Subchondral osteoclasts accelerate OA progression by mediating cartilage damage, promoting angiogenesis, and mediating neuropathic pain. With advancements in knowledge of bone biology and focused medicines, OA therapeutics for osteoclasts are gradually being revealed. This article presents an examination of the function and processes that regulate subchondral osteoclasts in OA, detailing recent breakthroughs in targeted therapy for osteoarthritis involving subchondral osteoclasts. The aim of this study is to address the current knowledge gap in OA treatment and promote the advancement of innovative therapeutic approaches. Notably, combining single-cell RNA sequencing (scRNA-seq) with traditional therapeutic approaches to investigate the gene expression patterns of osteoclasts in OA from both temporal and spatial dimensions may lead to the discovery of novel OA treatment targets. Keywords: osteoarthritis, osteoclast, pain, angiogenesis, single-cell sequencing