Injured bone-triggered osteokines secretion promotes diabetic wound healing.

Abstract

The treatment of severe diabetic foot remains a clinical challenge. While it is established that bone can exert systemic effects through the secretion of osteokines on other organs, whether this endocrine function can be harnessed to promote diabetic wound healing remains unexplored. Here, we investigate the impact of a bone injury strategy on diabetic wound healing, leveraging the body's innate regenerative capacity to stimulate osteokine release and influence remote skin wound repair. This study demonstrates that the tibial defect significantly accelerates ipsilateral diabetic foot skin wound healing. Mechanistically, we identify osteokines, platelet-derived growth factor-BB (PDGF-BB), as the key to initiating this process. Bone defect triggers a substantial release of PDGF-BB, which reaches the skin wound site via peripheral circulation. At the skin wound site, PDGF-BB mediates the secretion of keratinocyte growth factor (KGF) from fibroblasts via the PDGFRβ signaling pathway, thereby promoting the rapid re-epithelialization of epidermal cells through a paracrine pathway. Additionally, elevated PDGF-BB levels enhance the regeneration of CD31hi Emcnhi blood vessels within the wound. Importantly, we demonstrate the therapeutic potential of osteokines by showing that a collagen hydrogel loaded with osteokines promotes wound healing in diabetic mice. Our findings reveal a clear link between bone and skin wound healing, providing a therapeutic inspiration for chronic wounds that are difficult to treat locally.