Bone innervation and vascularization regulated by osteoclasts contribute to refractive pain-related behavior in the collagen antibody-induced arthritis model

ObjectiveRheumatoid arthritis is often characterized by eroded joints and chronic pain that outlasts disease activity. Whilst several reports show strong associations between bone resorption and nociception, the underlying mechanisms remain to be unraveled. Here, we used the collagen antibody-induced arthritis (CAIA) model to examine the contribution of osteoclasts in pain regulation. The antinociceptive effects of osteoclasts inhibitors and their mechanisms of actions involving bone vascularization and innervation were also explored. MethodsBALB/c female mice were subjected to CAIA by intravenous injection of a collagen type-II antibody cocktail, followed by intraperitoneal injection of lipopolysaccharide. Degree of arthritis, bone resorption, mechanical hypersensitivity, vascularization and innervation in the ankle joint were assessed. Animals were treated with osteoclast inhibitors, zoledronate and cathepsin K inhibitor (T06), and netrin-1 neutralizing antibody. Potential pronociceptive factors were examined in primary osteoclast cultures. ResultsCAIA induced local bone loss in the calcaneus with ongoing increased osteoclast activity during the inflammatory phase of the model, but not after inflammation has resolved. Mechanical hypersensitivity was reversed by zoledronate in late but not inflammatory phase CAIA. This effect was coupled to the ability of osteoclasts to modulate bone vascularization and innervation, which was inhibited by osteoclast inhibitors. CAIA-induced hypersensitivity in the late phase was also reversed by anti-netrin-1 antibody. ConclusionOsteoclasts induce pain-like behavior in the CAIA model independent of inflammation via effects on bone vascularization and innervation. Key messagesWhat is already known about this subject? O_LIPain and residual signs of erosive lesions are frequently present in rheumatoid arthritis (RA) patients with good disease control C_LIO_LIOsteoclasts can induce nociceptive signaling but the exact mechanism with respect to RA-induced pain is not clear C_LI What does this study add? O_LIThe pronociceptive actions of osteoclasts extend beyond flares of joint inflammation and erosive activity by increasing bone innervation, bone vascularization and netrin-1 release C_LIO_LIOsteoclast inhibitors and neutralizing netrin-1 antibodies reverse refractive pain-related behaviors in the collagen antibody-induced arthritis model C_LI How might this impact on clinical practice or future developments? O_LIThis study provides insights to the potential of osteoclast inhibition as a therapeutic strategy for persistent pain in RA C_LI