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

Research output: Contribution to journalArticle

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
StatePublished - Feb 1 2018

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Achilles Tendon
Tendons
Fibrocartilage
Mesenchymal Stromal Cells
Bone and Bones
Ligaments
Immobilization
Matrix Metalloproteinase 13
Antibodies
Bone Remodeling
Proteoglycans
Neutralizing Antibodies
Osteogenesis
Collagen
Bone Marrow
Enthesopathy
Phenotype
Injections
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

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Aberrant TGF-β activation in bone tendon insertion induces enthesopathy-like disease. / Wang, Xiao; Xie, Liang; Crane, Janet; Zhen, Gehua; Li, Fengfeng; Yang, Ping; Gao, Manman; Deng, Ruoxian; Wang, Yiguo; Jia, Xiaohua; Fan, Cunyi; Wan, Mei; Cao, Xu.

In: Journal of Clinical Investigation, Vol. 128, No. 2, 01.02.2018, p. 846-860.

Research output: Contribution to journalArticle

Wang, Xiao ; Xie, Liang ; Crane, Janet ; Zhen, Gehua ; Li, Fengfeng ; Yang, Ping ; Gao, Manman ; Deng, Ruoxian ; Wang, Yiguo ; Jia, Xiaohua ; Fan, Cunyi ; Wan, Mei ; Cao, Xu. / Aberrant TGF-β activation in bone tendon insertion induces enthesopathy-like disease. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 2. pp. 846-860.
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AU - Li, Fengfeng

AU - Yang, Ping

AU - Gao, Manman

AU - Deng, Ruoxian

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