Aberrant TGF-<strong>β</strong> activation in bone tendon insertion induces enthesopathy-like disease

Xiao Wang

Liang Xie

Janet Crane

Gehua Zhen

Yiguo Wang+4 authors

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^{Department of Orthopedic Surgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.}

^{State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.}

^{Department of Obstetrics and Gynecology, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China.}

^{Department of Spinal Surgery/Orthopedic Research Institute, First Affiliated Hospital, Sun Yat-sen University, Guandong, China.}

^{Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, China.}

^{Department of Orthopedic Surgery, Shanghai Sixth People’s Hospital, Shanghai, China.}

^{Corresponding author.}

Address correspondence to: Xu Cao, 720 Rutland Avenue, Ross 231, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. Phone: 410.502.6440; Email: ude.imhj@11oacx.

Xiao Wang: moc.liamg@gnaw.x.nuahs; Liang Xie: moc.qq@433711243; Janet Crane: ude.imhj@2enarcj; Gehua Zhen: ude.imhj@1nehzg; Fengfeng Li: moc.361@elamgnef; Ping Yang: moc.361@7215gnipgnay; Manman Gao: nc.ude.usys.2liam@mnamoag; Ruoxian Deng: ude.imhj@3gnedr; Yiguo Wang: ude.imhj@953gnawy; Xiaohua Jia: nc.ca.ai@aij.auhoaix; Cunyi Fan: nc.ude.utjs@nafyc; Mei Wan: ude.imhj@4nawm; Xu Cao: ude.imhj@11oacxAddress correspondence to: Xu Cao, 720 Rutland Avenue, Ross 231, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. Phone: 410.502.6440; Email: ude.imhj@11oacx.

Received 2017 Jul 10; Accepted 2017 Dec 7.

Abstract

Enthesopathy is a disorder of bone, tendon, or ligament insertion. It represents one-fourth of all tendon-ligament diseases and is one of the most difficult tendon-ligament disorders to treat. Despite its high prevalence, the exact pathogenesis of this condition remains unknown. Here, we show that TGF-β was activated in both a semi-Achilles tendon transection (SMTS) mouse model and in a dorsiflexion immobilization (DI) mouse model of enthesopathy. High concentrations of active TGF-β recruited mesenchymal stromal stem cells (MSCs) and led to excessive vessel formation, bone deterioration, and fibrocartilage calcification. Transgenic expression of active TGF-β1 in bone also induced enthesopathy with a phenotype similar to that observed in SMTS and DI mice. Systemic inhibition of TGF-β activity by injection of 1D11, a TGF-β–neutralizing antibody, but not a vehicle antibody, attenuated the excessive vessel formation and restored uncoupled bone remodeling in SMTS mice. 1D11-treated SMTS fibrocartilage had increased proteoglycan and decreased collagen X and matrix metalloproteinase 13 expression relative to control antibody treatment. Notably, inducible knockout of the TGF-β type II receptor in mouse MSCs preserved the bone microarchitecture and fibrocartilage composition after SMTS relative to the WT littermate controls. Thus, elevated levels of active TGF-β in the enthesis bone marrow induce the initial pathological changes of enthesopathy, indicating that TGF-β inhibition could be a potential therapeutic strategy.

Keywords: Bone Biology

Keywords: Bone disease

Abstract

Acknowledgments

This work was supported in part by NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases grants AR071432 and {"type":"entrez-nucleotide","attrs":{"text":"AR063943","term_id":"5993251","term_text":"AR063943"}}AR063943 (to XC).

Acknowledgments

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Version 1. 01/22/2018

Electronic publication

Version 2. 02/01/2018

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Footnotes

Conflict of interest: The authors have declared that no conflict of interest exists.

Reference information: J Clin Invest. 2018;128(2):846–860.https://doi.org/10.1172/JCI96186.

Footnotes

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