The HIF-1α/PLOD2 axis integrates extracellular matrix organization and cell metabolism leading to aberrant musculoskeletal repair  

作　　者：Heeseog Kang Amy L.Strong Yuxiao Sun Lei Guo Conan Juan Alec C.Bancroft Ji Hae Choi Chase A.Pagani Aysel A.Fernandes Michael Woodard Juhoon Lee Sowmya Ramesh Aaron W.James David Hudson Kevin N.Dalby Lin Xu Robert J.Tower Benjamin Levi 

机构地区：[1]Center for Organogenesis,Regeneration and Trauma,Department of Surgery,University of Texas Southwestern,Dallas,TX 75390,USA [2]Section of Plastic Surgery,Department of Surgery,University of Michigan,Ann Arbor,MI 48109,USA [3]Quantitative Biomedical Research Center,Peter O’Donnell Jr.School of Public Health,University of Texas Southwestern,Dallas,TX 75390,USA [4]Department of Orthopedics and Sports Medicine,University of Washington,Seattle,WA 98195,USA [5]Division of Chemical Biology and Medicinal Chemistry,College of Pharmacy,University of Texas at Austin,Austin,TX 78712,USA [6]Department of Pathology,Johns Hopkins University,Baltimore,MD 21218,USA

出　　处：《Bone Research》2024年第2期289-301,共13页骨研究（英文版）

基　　金：supported by NIH R01 AR078324 and R01 AR071379.

摘　　要：While hypoxic signaling has been shown to play a role in many cellular processes,its role in metabolism-linked extracellular matrix(ECM)organization and downstream processes of cell fate after musculoskeletal injury remains to be determined.Heterotopicossification(HO)is a debilitating condition where abnormal bone formation occurs within extra-skeletal tissues.Hypoxia andhypoxia-inducible factor 1α(HIF-1α)activation have been shown to promote HO.However,the underlying molecular mechanisms bywhich the HIF-1αpathway in mesenchymal progenitor cells(MPCs)contributes to pathologic bone formation remain to beelucidated.Here,we used a proven mouse injury-induced HO model to investigate the role of HIF-1αon aberrant cell fate.Usingsingle-cell RNA sequencing(scRNA-seq)and spatial transcriptomics analyses of the HO site,we found that collagen ECM organizationis the most highly up-regulated biological process in MPCs.Zeugopod mesenchymal cell-specific deletion of Hif1α(Hoxa11-CreER^(T2);Hif1a^(fl/fl))significantly mitigated HO in vivo.ScRNA-seq analysis of these Hoxa11-CreER^(T2);Hif1a^(fl/fl)mice identified the PLOD2/LOXpathway for collagen cross-linking as downstream of the HIF-1αregulation of HO.Importantly,our scRNA-seq data and mechanisticstudies further uncovered that glucose metabolism in MPCs is most highly impacted by HIF-1αdeletion.From a translational aspect,a pan-LOX inhibitor significantly decreased HO.A newly screened compound revealed that the inhibition of PLOD2 activity in MPCssignificantly decreased osteogenic differentiation and glycolytic metabolism.This suggests that the HIF-1α/PLOD2/LOX axis linked tometabolism regulates HO-forming MPC fate.These results suggest that the HIF-1α/PLOD2/LOX pathway represents a promisingstrategy to mitigate HO formation.

关 键 词：METABOLISM SKELETAL ABERRANT 

分 类 号：R68[医药卫生—骨科学]