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J Clin Invest. 2018 Feb 1;128(2):846-860. doi: 10.1172/JCI96186. Epub 2018 Jan 22.

Aberrant TGF-β activation in bone tendon insertion induces enthesopathy-like disease.

Author information

1
Department of Orthopedic Surgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
2
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
3
Department of Obstetrics and Gynecology, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China.
4
Department of Spinal Surgery/Orthopedic Research Institute, First Affiliated Hospital, Sun Yat-sen University, Guandong, China.
5
Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
6
Department of Orthopedic Surgery, Shanghai Sixth People's Hospital, Shanghai, China.

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; Bone disease

PMID:
29355842
PMCID:
PMC5785263
DOI:
10.1172/JCI96186
[Indexed for MEDLINE]
Free PMC Article

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