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

Abstract

Objective: Rheumatoid 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. Methods: BALB/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. Results: CAIA 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. Conclusion: Osteoclasts induce pain-like behavior in the CAIA model independent of inflammation via effects on bone vascularization and innervation. Keywords: pain, rheumatoid arthritis, osteoclast, vascularization, innervation

Metastatic infiltration of nervous tissue and periosteal nerve sprouting in multiple myeloma induced bone pain

“…Netrin-1 is an axon guidance molecule known to play a pivotal role in neurogenesis through binding to its canonical receptors UNC5 homolog (UNC5H) and deleted in colorectal cancer (DCC) (Madison et al, 2000; Dun and Parkinson, 2017; Boyer and Gupton, 2018). Previous studies have demonstrated a role of netrin-1 on sensory nerve sprouting (Zhu et al, 2019); moreover, silencing netrin-1 reduces hyperalgesia and CGRP+ nerve fiber sprouting in a rat model of disc degeneration (Zheng et al, 2023) and pharmacological netrin-1 inhibition with the NP-137 anti-netrin-1 antibody reduced hyperalgesia in an arthritis model (Rudjito et al, 2021). To investigate whether blockade of periosteal nerve sprouting attenuated MIBP, 5TGM1-GFP inoculated mice were systemically treated with vehicle (MM VEH ) or NP137 (MM NP137 ; 10 mg/kg, i.p).…”