ABSTRACT Chronic pain is the most prominent symptom of osteoarthritis (OA) and a key reason why patients seek medical help. Persistent pain at rest profoundly affects the quality of life and daily physical activity. Pain itself is a risk factor for the development of future functional decline and increasing pain is a predictor of physical functional limitation and disability. Osteoarthritic pain is thought to emanate from small myelinated or unmyelinated fibers in one or more tissues including synovium, ligament, subchondral bone, and meniscus. In clinic, subchondral bone marrow edema-like lesions (BMLs) visualized by MRI are highly correlated with OA pain. Thus, the observation suggests that the source of pain is likely from subchondral bone. The detailed mechanism how subchondral bone generates OA pain, however, is largely unknown. During OA progression, aberrant osteoclast (OC) bone resorption enlarges subchondral bone cavity, which promotes sensory innervation and leads to OA pain. PGE2 mediates sensory nerve regulation of bone density. PGE2 concentration in bone negatively correlated with bone density. Our pilot data showed PGE2 levels and sensory innervation significantly increased in the cavity of OA subchondral bone which resembles extreme low bone density as seen in osteoporosis. This prompted us to propose that high levels of PGE2 sensitize the highly specialized sensory neurons, nociceptors, in the subchondral bone to promote pain. During the pathogenesis of OA, senescent cells are increased in the subchondral bone with at least 40% being osteoclastic cells. We have recently shown that OC secrete Netrin-1, an axonal guidance molecule, to induce sensory nerve axon growth in the subchondral bone to mediate OA pain. Therefore, we hypothesize that enlarged subchondral bone cavity by senescent OCs elevates PGE2 levels and further enhances sensory innervation to mediate OA pain. To test the hypothesis, we will investigate the role of senescent OC in inducing subchondral bone cavity and sensory innervation. We will examine the role of subchondral bone cavity by senescent OC induced abnormal bone remodeling in the elevation of PGE2 and subsequent OA pain. We will then test the effect of eliminating senescent osteoclast on subchondral bone cavity and sensory innervation for OA pain by administration of senolytic drug ABT263 to OA mice. Finally, we will investigate the effect of rescuing subchondral bone remodeling on sensory innervation and OA pain. We have developed a novel conjugate that bone-specifically delivers a TGFβ inhibitor and OC inhibitor alendronate. The effect of this small molecule conjugate will be examined on sensory innervation in subchondral bone and OA pain.