Dysregulated JAK2 signaling delays fracture healing by enhancing STAT3/NF-κB signaling and inhibiting BMP2-mediated osteogenesis.

Aims

Fracture nonunion is increasingly recognized in metabolic disorders such as obesity and type 2 diabetes (T2D), yet the molecular mechanisms underlying impaired fracture healing remain incompletely understood. We investigated how dysregulated JAK2 signaling affects fracture repair under metabolic stress and conditions of sustained JAK2 activation.

Materials And Methods

We integrated bioinformatic analyses with multiple mouse models of obesity, T2D, and JAK2 overexpression. Osteogenic differentiation, callus maturation, trabecular microarchitecture, and mechanical properties were evaluated, together with changes in the JAK2-STAT3/NF-κB-BMP2 signaling axis. KEY

Findings

Both reduced JAK2 expression and excessive JAK2 activation impaired bone formation, indicating that appropriate JAK2 activity is required for effective fracture repair. In obesity and T2D, reduced JAK2 expression was associated with impaired osteogenic differentiation of bone mesenchymal stem cells. In contrast, JAK2 overexpression enhanced STAT3/NF-κB signaling, increased inflammatory activity, and suppressed BMP2 expression. These changes delayed endochondral ossification, resulted in a collagen-deficient callus, reduced bone volume fraction (BV/TV), and compromised the mechanical strength of the healing bone.

Significance

Effective fracture healing requires tightly regulated JAK2 signaling. Our findings identify bidirectional JAK2 dysregulation as a potential mechanism linking metabolic dysfunction and sustained JAK2 activation to impaired bone regeneration. This mechanism may also help explain the increased susceptibility to fracture-healing complications in patients with myeloproliferative neoplasms. Modulation of JAK2-mediated inflammatory signaling may therefore represent a potential therapeutic approach to improve fracture repair in metabolic and hematologic disorders.