Enpp1 mutations promote upregulation of hedgehog signaling in heterotopic ossification with aging.

Autor: He Z; Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 517108, China.; Department of Orthopaedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China., Zhu Z; Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 517108, China., Tang T; Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 517108, China., Wang F; Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 517108, China., Guo P; Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 517108, China., Li J; Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 517108, China., Tung NTC; Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama, 930-0194, Japan., Liang Q; Department of Spine Surgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, 518025, China., Liu S; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510062, China., Gao M; Department of Sport Medicine, Inst Translat Med, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, 518025, China. gaomanm@mail2.sysu.edu.cn., Liu X; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510062, China. liuxizhe@mail.sysu.edu.cn., Zhou Z; Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 517108, China. zhouzhy23@mail.sysu.edu.cn.
Jazyk: angličtina
Zdroj: Journal of bone and mineral metabolism [J Bone Miner Metab] 2024 Nov; Vol. 42 (6), pp. 681-698. Date of Electronic Publication: 2024 Aug 30.
DOI: 10.1007/s00774-024-01543-1
Abstrakt: Introduction: Heterotopic ossification of the tendon and ligament (HOTL) is a chronic progressive disease that is usually accompanied by thickening and ossification of ligaments and high osteogenic activity of the surrounding ligament tissue. However, the molecular mechanism of maintaining the cellular phenotype of HOTL remains unclear.
Materials and Methods: We first constructed a model of HOTL, Enpp1 flox/flox /EIIa-Cre mice, a novel genetic mouse system. Imaging, histological, and cell-level analyses were performed to investigate the progressive ossification of the posterior longitudinal ligament, Achilles tendons, and degeneration joints caused by Enpp1 deficiency.
Results: The results indicate that Enpp1 deficiency led to markedly progressive heterotopic ossification (HO), especially spine, and Achilles tendons, and was associated with progressive degeneration of the knees. The bone mass was decreased in the long bone. Furthermore, fibroblasts from Enpp1 flox/flox /EIIa-Cre mice had greater osteogenic differentiation potential following induction by osteogenesis, accompanied by enhanced hedgehog (Hh) signaling. In addition, fibroblast cells show senescence, and aggravation of the senescence phenotype by further osteogenic induction.
Conclusion: Our study indicated that with increasing age, mutations in Enpp1 promote ectopic ossification of spinal ligaments and endochondral ossification in tendons and further aggravate knee degeneration by upregulating hedgehog signaling.
Competing Interests: Declarations. Conflict of interest: The authors declared no potential conflicts of interest to this article's research, authorship and publication. Ethical approval: The studies were reviewed and approved by the Institutional Animal Care and Use Committee, Sun Yat-Sen University (No. 2020000147).
(© 2024. The Author(s).)
Databáze: MEDLINE
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