Year: 2026
Type: article
Abstract: 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, potentially improving ischemic fracture healing. Our results suggest that CDK8 impedes stromal cell differentiation and that its inhibition may be a clinically translatable approach to enhance ischemic fracture healing.
Source: npj Regenerative Medicine
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,190
Awards: G20355773, Regulators of Ischemic Fracture Healing, Targeting Pathological Angiogenesis after Joint Injury, G694184567, Autonomous RUNX2 suppression in genetically modified stem cell-derived chondrocytes as a disease modifying therapeutic for PTOA, Bioerodible corticosteroid microparticle-drug as an intra-articular drug delivery system for osteoarthritis therapy, Disruption of CD47 signaling promotes healing in ischemic fractures and bone allografts, Fibrosis, inflammation, and osteophyte formation in post-traumatic osteoarthritis, Michigan Integrative Musculoskeletal Health Core Center (Overall Application), University of Michigan Rogel Cancer Center Support Grant 2023-2028, Notch signaling and Bone Fracture Healing, Mapping the joint-nerve interactome of the knee, Cdk8 inhibition as a therapeutic intervention for ischemic fracture healing, CTSA Predoctoral T32 at the University of Michigan, Sustained Biomaterial-mediated Inhibition of R-spondin 2 to Target Pathological Wnt Signaling in Post-Traumatic Osteoarthritis, Fibrosis, inflammation, and osteophyte formation in post-traumatic osteoarthritis
OpenAlex ID: W4410433114