KLF2/PPARγ axis contributes to trauma-induced heterotopic ossification by regulating mitochondrial dysfunction

Trauma-induced heterotopic ossification (HO) is a complex disorder after musculoskeletal injury and characterized by aberrant extraskeletal bone formation. Recent studies shed light on critical role of dysregulated osteogenic differentiation in aberrant bone formation. Krupel-like factor 2 (KLF2) and peroxisome proliferator-activated receptor gamma (PPAR & gamma;) are master adapter proteins that link cellular responses to osteogenesis; however, their roles and relationships in HO remain elusive. Using a murine burn/tenotomy model in vivo, we identified elevated KLF2 and reduced PPAR & gamma; levels in tendon stem/progenitor cells (TSPCs) during trauma-induced HO formation. Both KLF2 inhibition and PPAR & gamma; promotion reduced mature HO, whereas the effects of PPAR & gamma; promotion were abolished by KLF2 overexpression. Additionally, mitochondrial dysfunction and reactive oxygen species (ROS) production also increased after burn/tenotomy, and improvements in mitochondrial function (ROS scavenger) could alleviate HO formation, but were abolished by KLF2 activation and PPAR & gamma; suppression by affecting redox balance. Furthermore, in vitro, we found increased KLF2 and decreased PPAR & gamma; levels in osteogenically induced TSPCs. Both KLF2 inhibition and PPAR & gamma; promotion relieved osteogenesis by improving mitochondrial function and maintaining redox balance, and effects of PPAR & gamma; promotion were abolished by KLF2 overexpression. Our findings suggest that KLF2/PPAR & gamma; axis exerts regulatory effects on trauma-induced HO through modulation of mitochondrial dysfunction and ROS production in TSPCs by affecting redox balance. Targeting KLF2/PPAR & gamma; axis and mitochondrial dysfunction can represent attractive approaches to therapeutic intervention in trauma-induced HO.