Targeting Activin A signaling to enhance bone repair

Bones patients decreased worldwide, improve and repair. are normally able to heal robustly after injury. However, this capacity can go awry in 5-10% of in the form f delayed or nonunion fractures, causing substantial morbidity, loss of productivity, and quality of life. Old age is a major risk factor. With the rising prevalence of geriatric fractures there is an urgent need to understand the bone repair mechanism and identify new therapies to fracture healing. Bone regeneration is an intricate and complex process involving various cell types growth factors. The periosteum houses mesenchymal progenitor cells that play a central r ole in skeletal Impaired activity of periosteal mesenchymal progenitors contributes to delayed healing in aging. o We recently performed an unbiased and comprehensive single-cell RNA sequencing (scRNA-seq) analysis of intact and fracture-injured periosteum in young adult mice and identified a novel mesenchymal progenitor population - termed proliferative progenitor cells (PPCs)- which rapidly and robustly expands post-fracture. PPCs exhibited myofibroblast-like features and occupied a transitional state along the differentiation trajectory from primitive mesenchymal progenitor cells (MPCs) to terminally differentiated osteoblasts and chondrocytes. Interestingly, PPCs highly expressed Activin A, a member of TGFβ superfamily of growth factors. Analyses of both mouse and human periosteum revealed a marked post-fracture increase of Activin A, which was significantly blunted in aged mice compared to young ones. In culture, Activin A stimulated the proliferation of periosteal mesenchymal progenitors and promoted their differentiation into myofibroblasts, chondrocytes, and osteoblasts. Using two bone injury models (fracture and drill hole), we obtained complementary evidence that bone repair is delayed by systemic administration of a neutralizing antibody against Activin A and accelerated by local delivery of Activin A. Our central hypothesis is that Activin A expressed by a myofibroblast-like mesenchymal subpopulation, the PPCs, at the early stage of bone healing is essential for regulating periosteal mesenchymal progenitors to stimulate bone regeneration. Our objectives are to define the roles of this effector in bone repair and develop approaches targeting its mode of action to treat delayed or nonunion fracture healing, particularly in aging. Our aims are to: 1) elucidate the cellular mechanism of Activin A action on bone healing by examining the repair process in mice with Activin A deficiency in various cell types, including PPCs; 2) delineate the molecular mechanism of Activin A action on bone healing by studying Activin A signaling components in fracture callus, primary periosteal mesenchymal progenitors, and aged fractures; 3) target Activin A pathway for accelerating bone repair by designing a new hydrogel drug delivery system. Our proposal. proof-of-concept multidisciplinary team has worked together to generate the exciting preliminary data for this If successful, this proposal will reveal the critical role of Activin A in bone regeneration and provide evidence for targeting this novel pathway in fracture therapy development. Project Number: 1R01AG099895-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Ling Qin (+1 co-PI) | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $723,105 | Activity Code: R01 | Study Section: Musculoskeletal Tissue Engineering Study Section[MTE] View on NIH RePORTER: https://reporter.nih.gov/project-details/11338487