Persistent pain, particularly at rest, profoundly affects quality of life and daily physical activity, especially in the elderly population. Pain itself is a risk factor for the development of future functional decline. Moreover, decrease in mobility in turn significantly increases the risk of many chronic diseases. Low back pain (LBP) is an extremely common health problem and affects roughly 80% of people during their life course and is the leading cause of activity limitation and work absence. Thus, spinal degeneration with LBP is one of the most prevalent diseases leading to a decline in mobility and frailty. Unfortunately, we still do not understand the source of LBP and there is no effective disease-modified therapy. Spinal amphiarthrodial joints are recognized as a functional unit, each of which exhibit unique responses to mechanical loading and degenerate with aging. Especially, vertebral endplates undergo ossification and become porous under unbalance mechanical forces or during aging. We have previously found a large number of osteoclasts in the porous sclerotic endplates in LBP patients and aged mice (spinal hypersensitivity model), suggesting active bone remodeling in endplates. We have also identified that over 70% of these osteoclasts are senescent cells, which have been reported to lead to age associated tissue dysfunction. Moreover, clinical and rodent animal studies demonstrated that nerve density was higher in porous endplates than that in normal endplates in LBP patients and animal models, suggesting that the aberrantly innervated endplates may be a source of LBP in patients and spinal hypersensitivity in mice. We have recently shown that osteoclasts secrete Netrin-1, an axonal guidance molecule, to induce sensory nerve axonal growth in the endplates. Reduction of osteoclasts inhibited the sensory innervation into endplates. Furthermore, we have demonstrated that during bone remodeling, prostaglandin E2 (PGE2) activates its EP4 receptor on sensory nerves to decrease sympathetic tone, which induced osteoblastic differentiation of mesenchymal stromal cells. Our pilot data showed senescent osteoclasts, PGE2 and Netrin-1 levels were significantly increased in porous endplates. Therefore, we are in a unique position to determine the role of sensory nerve dysregulation of the vertebral endplate as the driver of spinal functional unit degeneration with aging. We hypothesize that elevated PGE2 concentrations and sensory innervation in the porous EP induced by senescent OCs and their secretion of excessive Netrin-1 mediate spinal hypersensitivity in mice (LBP in patients). Specifically, we will first determine the effect of osteoclastic SnCs on spinal hypersensitivity (Aim 1). We will next investigate the mechanism of sensory innervation by senescent osteoclast-produced Netrin-1 in porous endplates (Aim 2). We will finally examine if the elevated PGE2 level in porous endplates induce spinal hypersensitivity during spine degeneration (Aim 3).