PTH Attenuation of Spinal Degeneration During Aging PI Janet Crane

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SUMMARY Low back pain is the leading cause of disability, driven predominantly by aging. Pain contributes to frailty by lowering quality of life and limiting physical activities. Intervertebral disc (IVD) degeneration is the most common cause of low back pain, but is a non-specific finding. No cause-directed, mechanism-based medications protect the spine from progression of degeneration and pain. The spine is a complex joint, built from alternating bony vertebrae and IVD. The vertebral endplate forms a structural boundary between the IVD and the vertebral body. Recent studies have implicated that the vertebral endplate plays a key role in the development of spinal degeneration and low back pain. We have recently reported that daily administration of parathyroid hormone (PTH) in aged mice for two months increases IVD cell size, restoring the vacuoles and rejuvenating the IVD. We have also found that cartilaginous endplates become ossified and porous during aging, which induces sensory innervation for spinal hypersensitivity. Our preliminary data demonstrates that endplate sclerosis improves with PTH administration. Most importantly, we have found that the aberrant innervation of the endplate is reversed with PTH and is associated with a reduction in pain behaviors in the IVD mouse models. We hypothesize that PTH stimulated anabolic bone formation remodels the sclerotic, porous EP to reduce aberrant nociceptive innervation. In this project, we will pursue the following specific aims: Aim 1: Examine vertebral endplate remodeling in the process of PTH-induced rejuvenation of IVD; Aim 2: Identify cellular target of PTH-induced remodeling of porous vertebral endplates; and Aim 3: Determine the mechanism of PTH-induced reduction of sensory innervation and improved pain behaviors. Our study team is comprised of basic scientists with expertise in bone biology regarding PTH cell signaling mechanisms and neuroscience regarding nociceptor neuronal activity, as well as, physician-scientists with translation expertise in mouse models of human disease, spinal degeneration, and clinical use of PTH. We are uniquely suited to further understand the mechanistic actions of PTH and potential as a disease modifying treatment of low back pain. Understanding the mechanism of PTH treatment of low back pain will provide necessary data to inform further drug development and clinical trial designs exploring activation of the PTH signaling pathway as a disease-modifying treatment of spinal degeneration. .