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

Abstract

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: angiogenesis; osteoarthritis; osteoclast; pain; single-cell sequencing.

Graphical abstract

Figure 1

Schematic representation of subchondral bone structure and osteoclast formation (A) The anatomical structure of a healthy knee; (B) The inset shows a magnified view of the microstructure of subchondral bone; (C) The process of OC formation. Created in BioRender. Chen, S. (2025) https://BioRender.com/a42j210.

Figure 2

Diagram of the role of OCs in regulating cartilage damage, angiogenesis, and pain in the OA microenvironment. Created in BioRender. Chen, S. (2025) https://BioRender.com/fb5aame.

Figure 3

Direct and indirect factors of cartilage damage mediated by OCs. Pre-osteoclasts can directly mediate cartilage injury through vascular invasion. Alternatively, mature osteoclasts may directly mediate cartilage damage by secreting lncRNA or miRNA. In addition, mature osteoclasts can mediate subchondral bone microfracture by affecting the mechanical stress of subchondral bone and secrete TGF-β1 to mediate bone remodeling, leading to stress imbalance in cartilage and indirectly affecting cartilage homeostasis. Created in BioRender. Chen, S. (2025) https://BioRender.com/s82g938.