A multi-functional small molecule alleviates fracture pain and promotes bone healing

Skeletal injuries are a major cause of morbidities worldwide with bone fractures accounting for a substantial portion. Patients suffering from bone fractures and undergoing surgery experience different levels of pain throughout the healing process requiring pain-mitigating interventions. Furthermore, a considerable number of bone fractures suffer from delayed healing, and unresolved acute pain may transition to chronic and maladaptive pain. Current management of pain involves treatment with NSAIDs and opioids, however, these analgesics have substantial drawbacks including delaying healing, systemic side effects, and potential for addiction. Hence, a therapeutic approach that concomitantly attenuates pain locally and actively promotes healing would address a significant clinical problem and improve the overall functional outcome for patients. Herein, we tested the hypothesis that the purine molecule, adenosine, could simultaneously alleviate fracture pain and promote healing by targeting different adenosine receptor subtypes in different cell populations. Our results demonstrate that local delivery of adenosine inhibited nociceptive activity of peripheral neurons through activation of adenosine A1 receptor (ADORA1) and mitigates pain. Concurrently, localization of adenosine at the fracture site also promoted osteogenic differentiation of mesenchymal stromal cells through adenosine A2B receptor (ADORA2B) and improved bone healing. Although further work is needed to extend the findings to human patients, this study provides evidence that the unique functional properties of adenosine along with its local delivery could provide an innovative, safe, and translatable therapeutic strategy to treat bone trauma and associated pain.One Sentence SummaryAdenosine as a therapeutic for fracture pain and healing