In this interesting paper, researchers investigate the mechanisms by which senolytics can reduce pain in osteoarthritis, while not affecting cartilage degeneration. This outcome appears to involve changes in sensitivity-related signaling that affects the behavior of the peripheral nervous system in and around the damaged areas of the joint. Cartilage is one of the least regenerative tissues in the body. The effective treatment of cartilage damage, it seems, will need more than merely removing the causes of damage to date, but also regenerative therapies to repair the existing damage.
Both clinical and preclinical research suggest that osteoarthritis (OA)-related pain is induced by increased nociceptive input from the joint through alterations in pain signaling pathways in the central and peripheral nervous system. For example, activation of nociceptive neurons in the dorsal root ganglion (DRG) through nerve growth factor (NGF) to activate nociceptive neurons by binding tropomyosin receptor kinase A (TrkA), chemokine (C-C motif) ligand 2 (CCL2), tumor necrosis factor (TNF), and Netrin-1 correlates with OA-related pain. Moreover, these axon guidance proteins induce nociceptive neuron projection locally in multiple joint tissues, including synovium and subchondral bone, leading to an exaggerated pain response.
Currently, it is unknown whether senolytic drugs affect the degree of innervation of sensory nerve fibers in the synovium and subchondral bone and if there are subsequent changes to nociceptive signaling pathways, like CGRP and NGF/TrkA, to alleviate OA-related joint pain. Here, we investigated the therapeutic potential of senolytics against a spontaneously developed OA. Using 21 and 22- month-old mice, we analyzed the effects of two senolytic drugs (ABT263 and the combination of dasatinib and quercetin) on structural alterations (including articular cartilage and subchondral bone degeneration and synovitis) and pain in knee joints. We further analyzed pain-related sensory innervation and axonal growth-promoting factors that stimulate neuronal sprouting in the joints and DRG and knee joint angiogenesis to address putative nociceptive mechanisms by which senolytic treatment reduces OA pain.
Selective elimination of the senescent cells that accumulated in the articular cartilage and synovium by these two drugs did not alter cartilage degeneration and abnormal bone changes during spontaneous OA progression. Treatment reduced thermal and mechanical hyperalgesia associated with OA and peripheral sensitization through decreased expression of axon guidance proteins (nerve growth factor NGF/TrkA) and nociceptive neuron (calcitonin gene-related peptide, CGRP) projection to the synovium, subchondral bone marrow, and dorsal root ganglion, and knee joint angiogenesis. We suggest that systemic administration of ABT263 and the dasatinib and quercetin combination is an exciting therapeutic approach to age-related OA pain.