The HIF-1α/PLOD2 axis integrates extracellular matrix organization and cell metabolism leading to aberrant musculoskeletal repair
Abstract 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. Heterotopic ossification (HO) is a debilitatin...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-03-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-024-00320-0 |
| _version_ | 1797259451936276480 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Heeseog Kang |
| collection | DOAJ |
| description | Abstract 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. Heterotopic ossification (HO) is a debilitating condition where abnormal bone formation occurs within extra-skeletal tissues. Hypoxia and hypoxia-inducible factor 1α (HIF-1α) activation have been shown to promote HO. However, the underlying molecular mechanisms by which the HIF-1α pathway in mesenchymal progenitor cells (MPCs) contributes to pathologic bone formation remain to be elucidated. Here, we used a proven mouse injury-induced HO model to investigate the role of HIF-1α on aberrant cell fate. Using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics analyses of the HO site, we found that collagen ECM organization is 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/LOX pathway for collagen cross-linking as downstream of the HIF-1α regulation of HO. Importantly, our scRNA-seq data and mechanistic studies further uncovered that glucose metabolism in MPCs is most highly impacted by HIF-1α deletion. From a translational aspect, a pan-LOX inhibitor significantly decreased HO. A newly screened compound revealed that the inhibition of PLOD2 activity in MPCs significantly decreased osteogenic differentiation and glycolytic metabolism. This suggests that the HIF-1α/PLOD2/LOX axis linked to metabolism regulates HO-forming MPC fate. These results suggest that the HIF-1α/PLOD2/LOX pathway represents a promising strategy to mitigate HO formation. |
| first_indexed | 2024-04-24T23:09:39Z |
| format | Article |
| id | doaj.art-bbe26278c92c4c7694b18c1d110b314f |
| institution | Directory Open Access Journal |
| issn | 2095-6231 |
| language | English |
| last_indexed | 2024-04-24T23:09:39Z |
| publishDate | 2024-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj.art-bbe26278c92c4c7694b18c1d110b314f2024-03-17T12:18:15ZengNature Publishing GroupBone Research2095-62312024-03-0112111310.1038/s41413-024-00320-0The HIF-1α/PLOD2 axis integrates extracellular matrix organization and cell metabolism leading to aberrant musculoskeletal repairHeeseog Kang0Amy L. Strong1Yuxiao Sun2Lei Guo3Conan Juan4Alec C. Bancroft5Ji Hae Choi6Chase A. Pagani7Aysel A. Fernandes8Michael Woodard9Juhoon Lee10Sowmya Ramesh11Aaron W. James12David Hudson13Kevin N. Dalby14Lin Xu15Robert J. Tower16Benjamin Levi17Center for Organogenesis, Regeneration and Trauma, Department of Surgery, University of Texas SouthwesternSection of Plastic Surgery, Department of Surgery, University of MichiganCenter for Organogenesis, Regeneration and Trauma, Department of Surgery, University of Texas SouthwesternQuantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas SouthwesternCenter for Organogenesis, Regeneration and Trauma, Department of Surgery, University of Texas SouthwesternCenter for Organogenesis, Regeneration and Trauma, Department of Surgery, University of Texas SouthwesternCenter for Organogenesis, Regeneration and Trauma, Department of Surgery, University of Texas SouthwesternCenter for Organogenesis, Regeneration and Trauma, Department of Surgery, University of Texas SouthwesternDepartment of Orthopedics and Sports Medicine, University of WashingtonCenter for Organogenesis, Regeneration and Trauma, Department of Surgery, University of Texas SouthwesternDivision of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas at AustinDepartment of Pathology, Johns Hopkins UniversityDepartment of Pathology, Johns Hopkins UniversityDepartment of Orthopedics and Sports Medicine, University of WashingtonDivision of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas at AustinQuantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas SouthwesternCenter for Organogenesis, Regeneration and Trauma, Department of Surgery, University of Texas SouthwesternCenter for Organogenesis, Regeneration and Trauma, Department of Surgery, University of Texas SouthwesternAbstract 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. Heterotopic ossification (HO) is a debilitating condition where abnormal bone formation occurs within extra-skeletal tissues. Hypoxia and hypoxia-inducible factor 1α (HIF-1α) activation have been shown to promote HO. However, the underlying molecular mechanisms by which the HIF-1α pathway in mesenchymal progenitor cells (MPCs) contributes to pathologic bone formation remain to be elucidated. Here, we used a proven mouse injury-induced HO model to investigate the role of HIF-1α on aberrant cell fate. Using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics analyses of the HO site, we found that collagen ECM organization is 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/LOX pathway for collagen cross-linking as downstream of the HIF-1α regulation of HO. Importantly, our scRNA-seq data and mechanistic studies further uncovered that glucose metabolism in MPCs is most highly impacted by HIF-1α deletion. From a translational aspect, a pan-LOX inhibitor significantly decreased HO. A newly screened compound revealed that the inhibition of PLOD2 activity in MPCs significantly decreased osteogenic differentiation and glycolytic metabolism. This suggests that the HIF-1α/PLOD2/LOX axis linked to metabolism regulates HO-forming MPC fate. These results suggest that the HIF-1α/PLOD2/LOX pathway represents a promising strategy to mitigate HO formation.https://doi.org/10.1038/s41413-024-00320-0 |
| spellingShingle | 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 The HIF-1α/PLOD2 axis integrates extracellular matrix organization and cell metabolism leading to aberrant musculoskeletal repair Bone Research |
| title | The HIF-1α/PLOD2 axis integrates extracellular matrix organization and cell metabolism leading to aberrant musculoskeletal repair |
| title_full | The HIF-1α/PLOD2 axis integrates extracellular matrix organization and cell metabolism leading to aberrant musculoskeletal repair |
| title_fullStr | The HIF-1α/PLOD2 axis integrates extracellular matrix organization and cell metabolism leading to aberrant musculoskeletal repair |
| title_full_unstemmed | The HIF-1α/PLOD2 axis integrates extracellular matrix organization and cell metabolism leading to aberrant musculoskeletal repair |
| title_short | The HIF-1α/PLOD2 axis integrates extracellular matrix organization and cell metabolism leading to aberrant musculoskeletal repair |
| title_sort | hif 1α plod2 axis integrates extracellular matrix organization and cell metabolism leading to aberrant musculoskeletal repair |
| url | https://doi.org/10.1038/s41413-024-00320-0 |
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