Accepted

The efficacy of mesenchymal stem cell (MSC) therapies is increasingly attributed to paracrine secretion, particularly exosomes. In this study, we investigated the role of MSC exosomes in the regulation of inflammatory response, nociceptive behaviour, and condylar cartilage and subchondral bone healing in an immunocompetent rat model of temporomandibular joint osteoarthritis (TMJ-OA). We observed that exosome-mediated repair of osteoarthritic TMJs was characterized by early suppression of pain and degeneration with reduced inflammation, followed by sustained proliferation and gradual improvements in matrix expression and subchondral bone architecture, leading to overall joint restoration and regeneration. Using chondrocyte cultures, we could attribute some of the cellular activities during exosome-mediated joint repair to adenosine activation of AKT, ERK and AMPK signalling. Specifically, MSC exosomes enhanced s-GAG synthesis impeded by IL-1β, and suppressed IL-1β-induced nitric oxide and MMP13 production. These effects were partially abrogated by inhibitors of adenosine receptor activation, AKT, ERK and AMPK phosphorylation. Together, our observations suggest that MSC exosomes promote TMJ repair and regeneration in OA through a well-orchestrated mechanism of action that involved multiple cellular processes to restore the matrix and overall joint homeostasis. This study demonstrates the translational potential of a cell-free ready-to-use exosome-based therapeutic for treating TMJ pain and degeneration.

Spinal cord lamina I neurons receiving dense input from nociceptors, and projecting to the parabrachial area at the ponto-mesencephalic junction form the major ascending pain-related pathway in rodents. Lamina I spinoparabrachial neurons have never been characterised in mice, despite the growing and extensive use of this species to understand the contribution of lamina I spinoparabrachial neurons in chronic pain. The electrophysiological properties of lamina I spinoparabrachial neurons recorded here in the anaesthetized mice are comparable to those of rat or cat, forming a nociceptive and thermoreceptive pathway. It was confirmed "on line" that lamina I spinoparabrachial neurons that normally encode noxious stimuli can receive input from low threshold mechanoreceptors in certain conditions. The present work indicates that the study of lamina I spinoparabrachial neurons in vivo could take advantage of the use of genetically modified mice.

Pain is the main reason patients report Osteoarthritis (OA), yet current analgesics remain relatively ineffective. This study investigated both peripheral and central mechanisms that lead to the development of OA associated chronic pain.