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

• Published in: The Journal of clinical investigation Vol. 128; no. 2; pp. 846 - 860
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.02.2018
• Subjects: Achilles tendon; Angiogenesis; Animals; Antibodies, Neutralizing - pharmacology; Arthritis; Biomedical research; Bone and Bones - pathology; Bone composition; Bone growth; Bone marrow; Bone Remodeling; Calcification; Cartilage - pathology; Collagen; Collagen (type X); Collagen - metabolism; Collagenase 3; Disease; Disease Models, Animal; Enthesopathy - pathology; Fibroblasts; Fibrocartilage - pathology; Growth factors; Immobilization; Ligaments; Male; Matrix metalloproteinase; Mesenchymal Stem Cells; Mesenchyme; Metalloproteinase; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Osteoclasts - metabolism; Pathogenesis; Phenotype; Phenotypes; Receptor, Transforming Growth Factor-beta Type II - genetics; Rodents; Signal Transduction; Sports injuries; Stem cell transplantation; Stem cells; Tendons; Tendons - metabolism; Tendons - pathology; Transforming Growth Factor beta - metabolism; Transforming growth factor-b1; X-Ray Microtomography; Bone Biology; Bone disease
• DOI: 10.1172/JCI96186
• ISSN: 0021-9738

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.