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

Abstract

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.

Lung Inflammatory Phenotype in Mice Deficient in Fibulin-2 and ADAMTS-12

“…In the latest participation of fibulin-2 acts by modulation of the inflammatory response; levels of inflammatory cells are significantly lower in the spleen and thymus in fibulin-2 -/animals. Furthermore, fibulin-2 seems to act also as an inhibitor of BMSCs osteogenesis through inhibition of the Notch2 pathway [57,58].…”

ZIF-8-Modified Black Phosphorus Nanosheets Incorporated into Injectable Dual-Component Hydrogels for Enhanced Photothermal Antibacterial and Osteogenic Activities

“…Consistent with the in vitro results, the bacterial colonies were almost eliminated when the GH-BZ hydrogel was exposed to NIR irradiation, indicating that the mild photothermal effect enhanced the antibacterial efficiency in vivo (Figure 8D). Severe inflammation caused by infection is an important factor affecting tissue and bone healing 60 and can have adverse effects on tissue-and bone-healing processes. Inflammatory cells are an important indicator of the degree of inflammation.…”

Matricellular proteins in immunometabolism and tissue homeostasis

“…Its influence is particularly prominent within the skeletal system, where it supports tissue development and homeostasis. Genetic deletion of fibulin-2 in murine models leads to enhanced mineralized bone formation and decreased bone resorption (203). Fibulin-3 has a role in the maintenance of vascular tissues.…”