Fig. 4
From: Mechanisms of bone pain: Progress in research from bench to bedside
The involvement of NETRIN1/DCC signaling pathway in different skeletal diseases. a NETRIN1 secreted by osteoclasts bind to its receptor, deleted in colorectal cancer (DCC), to induce sensory nerve axonal growth. NETRIN1 binding to DCC triggers cytoskeletal reorganization in the nerve axon via a number of intracellular signaling cascades. b Sclerotic and porous endplates are common pathological changes in LBP patients. Elevated NETRIN1 secretion by osteoclasts induces sensory innervation to the porous endplates. c In the pathological conditions of Ankylosing Spondylitis, active TGF-β levels are elevated due to excessive secretion by immune cells and osteoclasts bone resorption. A high-level of TGF-β recruits mesenchymal stromal cells (MSCs) resulting in vessels formation and osteoblasts differentiation. In the meantime, NETRIN1 secreted by osteoclasts may also contributes to sensory innervation and bone pain. d Increased aberrant subchondral bone remodeling occurs during OA progression. Elevated osteoclast activity and osteoclast-derived NETRIN1 induces sensory innervation to the subchondral bone and OA pain. e Increased osteoclast activity and bone disruption is a typical phenotype of skeletal autoimmune diseases. Inflammatory cytokines released by the immune cells promote osteoclastogenesis and osteoclast maturation. NETRIN1 released by osteoclasts induces sensory innervation to the afflicted joint
