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

Xiao Wang, Liang Xie, Janet Crane, Gehua Zhen, Fengfeng Li, Ping Yang, Manman Gao, Ruoxian Deng, Yiguo Wang, Xiaohua Jia, Cunyi Fan, Mei Wan, Xu Cao

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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.

Original languageEnglish (US)
Pages (from-to)846-860
Number of pages15
JournalJournal of Clinical Investigation
Volume128
Issue number2
DOIs
Publication statusPublished - Feb 1 2018

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ASJC Scopus subject areas

  • Medicine(all)

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