Abstract
BackgroundIncreased bone resorption is driven by augmented osteoclast activity in pathological states of the bone, including osteoporosis, fracture and metastatic bone cancer. Pain is a frequent co‐morbidity in bone pathologies and adequate pain management is necessary for symptomatic relief. Bone cancer is associated with severe skeletal pain and dysregulated bone remodelling, while increased osteoclast activity and bone pain are also observed in osteoporosis and during fracture repair. However, the effects of altered osteoclast activity and bone resorption on nociceptive processing of bone afferents remain unclear.MethodsThis study investigates whether physiologic osteoclasts and resulting changes in bone resorption can induce skeletal pain. We first assessed correlation between changes in bone microarchitecture (through µCT) and skeletal pain using standardized behavioural phenotyping assays in a mouse model of metastatic bone cancer. We then investigated whether increased activity of physiologic osteoclasts, and the associated bone resorption, is sufficient to induce skeletal pain using mouse models of localized and widespread bone resorption following administration of exogenous receptor activator of nuclear factor kappa‐B ligand (RANKL).ResultsOur data demonstrates that mice with bone cancer exhibit progressive pain behaviours that correlate with increased bone resorption at the tumour site. Systemic RANKL injections enhance osteoclast activity and associated bone resorption, without producing any changes in motor function or pain behaviours at both early and late timepoints.ConclusionThese findings suggest that activation of homeostatic osteoclasts alone is not sufficient to induce skeletal pain in mice.Significance statementThe role of osteoclasts in peripheral sensitization of sensory neurones is not fully understood. This study reports on the direct link between oestrogen‐independent osteoclast activation and skeletal pain. Administration of exogenous receptor activator of nuclear factor kappa‐B ligand (RANKL) increases bone resorption, but does not produce pro‐nociceptive changes in behavioural pain thresholds. Our data demonstrates that physiologic osteoclasts are not essential for skeletal pain behaviours.
Highlights
Several pathological bone conditions, including metastatic bone cancer, osteoporosis and fracture repair, are characterized by increased bone resorption and structural changes in bone microarchitecture
Cancer-induced bone pain (CIBP) is a unique and complex condition that occurs as result of primary tumours metastasizing to the bone and involves mechanisms that are characteristic of inflammation, neuropathy, nerve compression and ischaemia (Falk & Dickenson, 2014; Honore & Mantyh, 2000)
We found a substantial reduction in % bone volume (BV)/total volume (TV) (Welch's t-test, **p = .0227), bone surface (BS)/TV (Welch's t-test, **p = .0220), Tb.N. (Welch's t-test, **p = .0050) and Conn.D. (Welch's t-test, **p = .0069) in female mice
Summary
Several pathological bone conditions, including metastatic bone cancer, osteoporosis and fracture repair, are characterized by increased bone resorption and structural changes in bone microarchitecture. Pharmacological agents that target osteoclasts include bisphosphonates and denosumab, the latter an inhibitor of receptor activator of nuclear factor kappa-B ligand (RANKL), which is involved in osteoclast differentiation (Kong et al, 1999; Matsuzaki et al, 1998) Both bisphosphonates and denosumab are clinically licensed drugs that reduce bone loss, and in some cancer patients relieve pain (Body et al, 2004; Lipton & Balakumaran, 2012). Prolonged administration of bisphosphonates in rats impairs fracture healing (Savaridas et al, 2013), whereas a single bolus does not delay fracture repair (McDonald et al, 2008) These observations suggest that osteoclast activity is important throughout the healing process. We administered exogenous RANKL, locally within the femur and systemically, to induce bone resorption through physiologic osteoclast activation and assessed the effects on pain behaviour
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