Inhibition of CDK8 rescues impaired ischemic fracture healing

Annually, 10% of 15 million bone fractures in the US fail to heal, and fractures with compromised blood flow, i.e. ischemia, are five times more likely to become nonunions. While ischemia is known to impair healing, the cellular and molecular mechanisms underlying this deficiency are unclear. Wild-type mice with surgically-induced ischemia underwent tibia fractures, and single-cell RNA-sequencing was performed on calluses at days 4 and 7 post-fracture. We observed delayed chondrogenic differentiation and upregulation of Cyclin-Dependent Kinase 8 ( Cdk8) by stromal progenitors and fibroblasts in the ischemic callus. Hypoxia induced CDK8 gene expression in human mesenchymal stromal cells (hMSC), and pharmacological CDK8 inhibition promoted hMSC chondrogenic and osteogenic potential. In vivo oral delivery of a CDK8 inhibitor enhanced callus chondrogenesis and mineralization, and improved ischemic fracture healing. Our results suggest that CDK8 impedes stromal cell differentiation and that CDK8 inhibition is a clinically-translatable approach to enhance ischemic fracture healing.