Project Summary Intervertebral disc degeneration is a major etiological factor of low back pain, which is the #1 cause of job disability worldwide that affects 80% of people at least once in their lifetime. Older individuals are prone to intervertebral disc degeneration by a loss of disc height and hydration. Pain can worsen intervertebral disc degeneration by limiting mobility and reducing the mechanical forces necessary for homeostasis. Therefore, there is an unmet need to safely protect older individuals from intervertebral disc degeneration and, here, we intend to repurpose existing bone therapeutics to reduce/prevent intervertebral disc loss and consequently back pain in the aging population. Intervertebral disc degeneration remains a growing problem because (1) the US geriatric population is projected to outnumber children for the first time in history, (2) the early treatment of intervertebral disc degeneration remains palliative and (3) the ballooning socioeconomic burden. We are uniquely positioned to bridge the knowledge gap in the molecular mechanisms of bone therapeutics to stem intervertebral disc degeneration. Aging and mechanical injury of the intervertebral disc by compression both exacerbate breakdown of the extracellular matrix, but compression stimulates inflammation more so than aging. By contrast, we recently found that deletion of the inhibitor of Wnt/β-Catenin signaling sost, a bone formation anabolic mechanism and the genetic analog approach to anti-sclerostin antibody injection, increases the structural properties and hydration of the intervertebral disc. Another bone therapeutic that shows benefits to the intervertebral disc is anti-resorptive raloxifene, a non-uterine-targeting estrogen agonist, that also increases binding of water to collagen. Use of raloxifene in postmenopausal women is associated with relieving back pain and greater intervertebral disc height than non-treated women. Our studies show that raloxifene increases intervertebral disc height in male and female mice, reduces sex- and age-related intervertebral disc degeneration in female mice, improves metrics of pain-related behavior in old mice and stimulates Wnt and estrogen signaling. Here, we hypothesize that currently available therapeutics will stimulate extracellular matrix anabolism and prevent compression-induced intervertebral disc degeneration in young and aged mice. To test this hypothesis, we propose two aims using aged mice and catabolic compression as models of intervertebral disc degeneration. In aim 1, we will determine whether therapeutics known to activate Wnt signaling will prevent IVD degeneration by injurious mechanical compression in young and aged mice. In aim 2, we will determine whether estrogen signaling prevents IVD degeneration via Wnt signaling and whether prevention can be safely improved by combining the signaling pathways in aged mice. This proposal will repurpose current FDA-approved bone prophylactics that target pathways ...