STIMULATING BONE MARROW ADIPOCYTES LIPOLYSIS FOR ENHANCED FRACTURE HEALING

Bone nonunion poses a formidable clinical challenge necessitating urgent resolution, with its etiology intricately linked to disturbances within the bone microenvironment. A pivotal contributor to this microenvironmental disruption is bone marrow adipose tissue (BMAT), known for its secretion of inflammatory factors and elevation of reactive oxygen species (ROS) levels. Despite the acknowledged significance of BMAT, the association between BMAT lipolysis and bone fracture healing remains elusive. In the present study, we firstly demonstrated the inverse correlation between BMAT accumulation and the progression of fracture healing. Subsequently, we introduce a novel hydrogel system (Ma-Zn COF@Gel) designed for the efficient transport and release of Zn2+ and magnolol (Ma), aiming to stimulate BMAT lipolysis and enhance the functionality of cells crucial to bone healing. Mechanistically, Zn2+ instigates the activation of the PKA/HSL pathway, while Ma induces the activation of the ERK/HSL pathway within BMAT cells. These pathways collectively augment lipolysis, subsequently fostering M2 macrophage polarization, bone marrow-derived mesenchymal stem cell (BMSC) osteogenic differentiation, and endothelial cell angiogenesis. Conclusively, our study proposes a strategic approach targeting the activation of bone marrow adipocytes. This intervention aims to reprogram BMAT activity, restore the pro-regeneration bone microenvironment, and thereby expedite the process of fracture healing. The findings of the present study enhance our understanding of therapeutic strategies in the ongoing development of treatments for addressing bone nonunion.