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Aberrant TGF-β activation in bone tendon insertion induces enthesopathy-like disease
Xiao Wang, … , Mei Wan, Xu Cao
Xiao Wang, … , Mei Wan, Xu Cao
Published January 22, 2018
Citation Information: J Clin Invest. 2018;128(2):846-860. https://doi.org/10.1172/JCI96186.
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Research Article Bone Biology

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

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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.

Authors

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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Figure 1

Osteoclastic bone resorption in SMTS enthesopathy mice.

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Osteoclastic bone resorption in SMTS enthesopathy mice.
(A) μCT images o...
(A) μCT images of the PCT (sagittal view). Red arrowhead indicates altered morphology of the PCT. Red asterisk indicates bone marrow cavities. Scale bar: 500 μm. (B) Quantitative analysis of BV/TV, Tb.Th, Tb.N, Tb.Sp, and Tb.Pf in PCT determined by μCT analysis. (C) TRAP staining (magenta) in mouse PCT bone marrow. Scale bar: 200 μm. Red asterisks indicate bone marrow cavities. (D) Quantitative analysis of TRAP+ OCS/BS. (E) Quantitative analysis of active TGF-β1 in serum by ELISA. D0, prior to SMTS surgery; Sham, sham surgery; W1, 1 week after SMTS surgery. Data shown as mean ± SEM. n = 10. *P < 0.05 compared with the sham group.
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