The Pathogenetic Role of RANK/RANKL/OPG Signaling in Osteoarthritis and Related Targeted Therapies

Abstract

Background: Osteoarthritis (OA) is the most common degenerative joint disease and affects millions of people worldwide, particularly the elderly population. The pathophysiology of OA is complex and involves multiple factors. Methods: Several studies have emphasized the crucial role of inflammation in this process. The receptor activator of NF-κB ligand (RANKL), the receptor activator of NF-κB (RANK), and osteoprotegerin (OPG) trigger a signaling cascade that leads to the excessive production of RANKL in the serum. Conclusions: The aim of this narrative review is (i) to assess the role of the RANK/RANKL/OPG signaling pathway in the context of OA progression, focusing especially on the physiopathology and on all the mechanisms leading to the activation of the inflammatory cascade, and (ii) to evaluate all the potential therapeutic strategies currently available that restore balance to bone formation and resorption, reducing structural abnormalities and relieving pain in patients with OA.

Keywords: OPG; RANKL; denosumab; hyaluronic acid; joint disease; osteoarthritis; targeted therapies.

Figure 1

Potential mechanisms underlying signaling pathway crosstalk in OA. The RANK/RANKL/OPG pathway regulates the balance between bone formation and resorption, maintaining bone density and strength.

Figure 2

Clinical evidence of different phenotypes of OA. The image shows the difference between a healthy joint and one affected by osteoarthritis. The main pathophysiological processes that occur in osteoarthritis are illustrated in the figure.