Fibulin2: a negative regulator of BMSC osteogenic differentiation in infected bone fracture healing

Bone fracture remains a common occurrence, with a population-weighted incidence of approximately 3.21 per 1000. In addition, approximately 2% to 50% of patients with skeletal fractures will develop an infection, one of the causes of disordered bone healing. Dysfunction of bone marrow mesenchymal stem cells (BMSCs) plays a key role in disordered bone repair. However, the specific mechanisms underlying BMSC dysfunction caused by bone infection are largely unknown. In this study, we discovered that Fibulin2 expression was upregulated in infected bone tissues and that BMSCs were the source of infection-induced Fibulin2. Importantly, Fibulin2 knockout accelerated mineralized bone formation during skeletal development and inhibited inflammatory bone resorption. We demonstrated that Fibulin2 suppressed BMSC osteogenic differentiation by binding to Notch2 and inactivating the Notch2 signaling pathway. Moreover, Fibulin2 knockdown restored Notch2 pathway activation and promoted BMSC osteogenesis; these outcomes were abolished by DAPT, a Notch inhibitor. Furthermore, transplanted Fibulin2 knockdown BMSCs displayed better bone repair potential in vivo. Altogether, Fibulin2 is a negative regulator of BMSC osteogenic differentiation that inhibits osteogenesis by inactivating the Notch2 signaling pathway in infected bone. Bone fracture: Identifying a protein that hinders repair during infection A protein that is overexpressed during bone fracture infection blocks a key signaling pathway and prevents bone repair. Infection following bone fracture remains a leading cause of delayed or unsuccessful healing. Stem cells from bone marrow are the main source of osteoblasts, bone-forming cells necessary for healthy bone regeneration and repair. Infection causes disruption to stem cell function and hinders bone healing, but the exact mechanisms involved remain unclear. In experiments on human tissue samples and a mouse model, Jun Fei and Xiang Xu at the Army Medical University in Chongqing, China, and co-workers examined the role of the fibulin2 protein in infected bone fractures. Fibulin2 is overexpressed in infected tissues, and the protein suppresses stem cell differentiation into osteoblasts by deactivating a key signaling pathway. Blocking fibulin2 in mice models restored bone formation.