Osteoarthritis (OA) is a major cause of pain and disability and there are currently no treatments that reverse the joint deterioration with OA. The current standard of care involves pain management and ultimately, joint replacement surgery for advanced OA. A recent strategy to treat OA pain is focused on inhibition of nerve growth factor (NGF), a major mediator of nociceptive pain in OA. NGF antibodies effectively reduce OA pain; however, a small percentage of patients treated with anti-NGF antibodies develop a rapidly progressive/ destructive OA (RPOA) of the knee and hip that requires joint replacement; however, the precise etiology of RPOA is unclear. The long term goal of this collaboration is to understand the pathophysiology of RPOA and identify strategies to prevent it. NGF upregulates ion channels, receptors for inflammatory mediators, and signaling neuropeptides, including substance P (SP) and calcitonin gene-related peptide (CGRP) in sensory neurons and can enhance the outgrowth and branching of peripheral axons: both effects likely contribute to OA pain and underscore the mechanism by which anti-NGF antibodies achieve antinociception. In addition to their role in detecting pain via orthodromic neurotransmitter release; however, sensory neurons also can affect peripheral tissues through the antidromic release of neurotransmitters into the local microenvironment. In the joint, neuronal release of CGRP stimulates bone formation, reduces bone resorption and stimulates angiogenesis and vasodilatation of blood vessels. Based on this novel role of CGRP, we hypothesize that local release of CGRP in the subchondral bone is required for maintenance of bloodflow and bone formation in the OA joint, and that loss of CGRP signaling, induced by anti-NGF, facilitates accelerated degeneration of the OA joint by compromising subchondral bone integrity. The risk for RPOA is increased by high doses of anti-NGF antibodies, concomitant NSAID use and low bone mineral density caused by low estrogen levels, all factors that diminish the neuronal release of CGRP, supporting the notion that local CGRP could be protective against progressive OA. In Aim 1, we will determine the effects of anti-NGF therapy, in the absence and presence of NSAIDs, on the severity of knee OA in aged male and female mice. We will test the hypothesis that treatment with anti-NGF and NSAIDs reduce CGRP in subchondral bone in animals with surgical destabilization of the medial meniscus (DMM), resulting in altered subchondral bone mass and trabecular structure, and that this is associated with knee OA severity. If successful, Aim 1 will generate the first animal model of RPOA. In Aim 2, we will determine if anti-CGRP treatment will recapitulate the degeneration of the OA joint induced by anti-NGF therapy in aged female mice with DMM to test the hypothesis that inhibition of CGRP signaling compromises the integrity of subchondral bone in the animal model of OA. These studies will help to id...