Document 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.
Digital Object Identifier (DOI)
Publication Info
Published in npj Regenerative Medicine, Volume 11, 2026.
Rights
This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
APA Citation
Capobianco, C. A., Song, M. J., Farrell, E. C., Knights, A. J., Kessell, K., Donneys, A., Schmanski, J. T., Schroeder, L. R., Chen, M., Roninson, I. B., Wagley, Y., Maerz, T., & Hankenson, K. D. (2026). Inhibition of CDK8 rescues impaired ischemic fracture healing. Npj Regenerative Medicine, 11.https://doi.org/10.1038/s41536-026-00456-z