Load-induced regulation of tendon homeostasis by SPARC, a genetic predisposition factor for tendon and ligament injuries

Tendons and tendon interfaces have a very limited regenerative capacity, rendering their injuries clinically challenging to resolve. Tendons sense muscle-mediated load; however, our knowledge on how loading affects tendon structure and functional adaption remains fragmentary. Here, we provide eviden...

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Published inScience translational medicine Vol. 13; no. 582
Main Authors Wang, Tao, Wagner, Andrea, Gehwolf, Renate, Yan, Wenjin, Passini, Fabian S, Thien, Christine, Weissenbacher, Nadja, Lin, Zhen, Lehner, Christine, Teng, Huajian, Wittner, Claudia, Zheng, Qiujian, Dai, Jin, Ni, Ming, Wang, Allan, Papadimitriou, John, Leys, Toby, Tuan, Rocky S, Senck, Sasha, Snedeker, Jess G, Tempfer, Herbert, Jiang, Qing, Zheng, Ming H, Traweger, Andreas
Format Journal Article
LanguageEnglish
Published United States 24.02.2021
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Abstract Tendons and tendon interfaces have a very limited regenerative capacity, rendering their injuries clinically challenging to resolve. Tendons sense muscle-mediated load; however, our knowledge on how loading affects tendon structure and functional adaption remains fragmentary. Here, we provide evidence that the matricellular protein secreted protein acidic and rich in cysteine (SPARC) is critically involved in the mechanobiology of tendons and is required for tissue maturation, homeostasis, and enthesis development. We show that tendon loading at the early postnatal stage leads to tissue hypotrophy and impaired maturation of Achilles tendon enthesis in mice. Treadmill training revealed a higher prevalence of spontaneous tendon ruptures and a net catabolic adaptation in mice. Tendon hypoplasia was attenuated in mice in response to muscle unloading with botulinum toxin A. In vitro culture of three-dimensional tendon constructs showed load-dependent impairment of ribosomal S6 kinase activation, resulting in reduced type I collagen synthesis. Further, functional calcium imaging revealed that lower stresses were required to trigger mechanically induced responses in tendon fascicles. To underscore the clinical relevance of the findings, we further demonstrate that a missense mutation (p.Cys130Gln) in the follistatin-like domain of , which causes impaired protein secretion and type I collagen fibrillogenesis, is associated with tendon and ligament injuries in patients. Together, our results demonstrate that SPARC is a key extracellular matrix protein essential for load-induced tendon tissue maturation and homeostasis.
AbstractList Tendons and tendon interfaces have a very limited regenerative capacity, rendering their injuries clinically challenging to resolve. Tendons sense muscle-mediated load; however, our knowledge on how loading affects tendon structure and functional adaption remains fragmentary. Here, we provide evidence that the matricellular protein secreted protein acidic and rich in cysteine (SPARC) is critically involved in the mechanobiology of tendons and is required for tissue maturation, homeostasis, and enthesis development. We show that tendon loading at the early postnatal stage leads to tissue hypotrophy and impaired maturation of Achilles tendon enthesis in mice. Treadmill training revealed a higher prevalence of spontaneous tendon ruptures and a net catabolic adaptation in mice. Tendon hypoplasia was attenuated in mice in response to muscle unloading with botulinum toxin A. In vitro culture of three-dimensional tendon constructs showed load-dependent impairment of ribosomal S6 kinase activation, resulting in reduced type I collagen synthesis. Further, functional calcium imaging revealed that lower stresses were required to trigger mechanically induced responses in tendon fascicles. To underscore the clinical relevance of the findings, we further demonstrate that a missense mutation (p.Cys130Gln) in the follistatin-like domain of , which causes impaired protein secretion and type I collagen fibrillogenesis, is associated with tendon and ligament injuries in patients. Together, our results demonstrate that SPARC is a key extracellular matrix protein essential for load-induced tendon tissue maturation and homeostasis.
Author Lin, Zhen
Papadimitriou, John
Ni, Ming
Senck, Sasha
Zheng, Ming H
Jiang, Qing
Wang, Tao
Snedeker, Jess G
Thien, Christine
Zheng, Qiujian
Wagner, Andrea
Passini, Fabian S
Leys, Toby
Weissenbacher, Nadja
Wittner, Claudia
Traweger, Andreas
Lehner, Christine
Wang, Allan
Yan, Wenjin
Gehwolf, Renate
Tuan, Rocky S
Tempfer, Herbert
Dai, Jin
Teng, Huajian
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  givenname: Tao
  orcidid: 0000-0001-6899-7255
  surname: Wang
  fullname: Wang, Tao
  organization: Division of Orthopaedic Surgery, Department of Surgery, Guangdong Provincial People'sHospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510000, China
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  organization: Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
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  surname: Gehwolf
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  organization: Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
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  organization: State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
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  organization: Centre for Orthopaedic Translational Research, Medical School, University of Western Australia, Nedlands, Western Australia 6009,Australia
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  organization: Division of Orthopaedic Surgery, Department of Surgery, Guangdong Provincial People'sHospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510000, China
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  givenname: Huajian
  orcidid: 0000-0002-6441-2739
  surname: Teng
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  organization: Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing 210008, China
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  givenname: Claudia
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  givenname: Qiujian
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  surname: Zheng
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  organization: Division of Orthopaedic Surgery, Department of Surgery, Guangdong Provincial People'sHospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510000, China
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  givenname: Jin
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  surname: Dai
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  givenname: Ming
  orcidid: 0000-0002-3910-0127
  surname: Ni
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  organization: Department of Orthopaedics, General Hospital of Chinese People's Liberation Army, Beijing 100853, China
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  orcidid: 0000-0002-7902-9177
  surname: Wang
  fullname: Wang, Allan
  organization: Centre for Orthopaedic Translational Research, Medical School, University of Western Australia, Nedlands, Western Australia 6009,Australia
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  surname: Papadimitriou
  fullname: Papadimitriou, John
  organization: PathWest Laboratories, Nedlands, Western Australia 6009, Australia
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  givenname: Toby
  surname: Leys
  fullname: Leys, Toby
  organization: Centre for Orthopaedic Translational Research, Medical School, University of Western Australia, Nedlands, Western Australia 6009,Australia
– sequence: 18
  givenname: Rocky S
  orcidid: 0000-0001-6067-6705
  surname: Tuan
  fullname: Tuan, Rocky S
  organization: Institute for Tissue Engineering and Regenerative Medicine, Chinese University of Hong Kong, Hong Kong SAR, China
– sequence: 19
  givenname: Sasha
  orcidid: 0000-0001-8400-5121
  surname: Senck
  fullname: Senck, Sasha
  organization: Computed Tomography Research Group, University of Applied Sciences Upper Austria, 4600 Wels, Austria
– sequence: 20
  givenname: Jess G
  orcidid: 0000-0002-8115-0275
  surname: Snedeker
  fullname: Snedeker, Jess G
  organization: Institute for Biomechanics, ETH Zurich, 8008 Zürich, Switzerland
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  givenname: Qing
  orcidid: 0000-0002-2552-9686
  surname: Jiang
  fullname: Jiang, Qing
  email: andreas.traweger@pmu.ac.at, minghao.zheng@uwa.edu.au, qingj@nju.edu.cn
  organization: State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. andreas.traweger@pmu.ac.at minghao.zheng@uwa.edu.au qingj@nju.edu.cn
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  givenname: Ming H
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  surname: Zheng
  fullname: Zheng, Ming H
  email: andreas.traweger@pmu.ac.at, minghao.zheng@uwa.edu.au, qingj@nju.edu.cn
  organization: Perron Institute for Neurological and Translational Science, Nedlands, Western Australia 6009, Australia
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  surname: Traweger
  fullname: Traweger, Andreas
  email: andreas.traweger@pmu.ac.at, minghao.zheng@uwa.edu.au, qingj@nju.edu.cn
  organization: Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
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Snippet Tendons and tendon interfaces have a very limited regenerative capacity, rendering their injuries clinically challenging to resolve. Tendons sense...
SourceID pubmed
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SubjectTerms Animals
Genetic Predisposition to Disease
Homeostasis
Humans
Ligaments
Mice
Mice, Knockout
Osteonectin - genetics
Tendons - physiology
Title Load-induced regulation of tendon homeostasis by SPARC, a genetic predisposition factor for tendon and ligament injuries
URI https://www.ncbi.nlm.nih.gov/pubmed/33627488
Volume 13
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