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抑制过度活跃的 TGF-β 可减轻小鼠异位骨化的进展。

Inhibition of overactive TGF-β attenuates progression of heterotopic ossification in mice.

机构信息

Department of Orthopedic Surgery, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA.

Department of Orthopedic Surgery, Shanghai Sixth People's Hospital, 200030, Shanghai, China.

出版信息

Nat Commun. 2018 Feb 7;9(1):551. doi: 10.1038/s41467-018-02988-5.

DOI:10.1038/s41467-018-02988-5
PMID:29416028
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5803194/
Abstract

Acquired heterotopic ossification (HO) is a painful and debilitating disease characterized by extraskeletal bone formation after injury. The exact pathogenesis of HO remains unknown. Here we show that TGF-β initiates and promotes HO in mice. We find that calcified cartilage and newly formed bone resorb osteoclasts after onset of HO, which leads to high levels of active TGF-β that recruit mesenchymal stromal/progenitor cells (MSPCs) in the HO microenvironment. Transgenic expression of active TGF-β in tendon induces spontaneous HO, whereas systemic injection of a TGF-β neutralizing antibody attenuates ectopic bone formation in traumatic and BMP-induced mouse HO models, and in a fibrodysplasia ossificans progressive mouse model. Moreover, inducible knockout of the TGF-β type II receptor in MSPCs inhibits HO progression in HO mouse models. Our study points toward elevated levels of active TGF-β as inducers and promoters of ectopic bone formation, and suggest that TGF-β might be a therapeutic target in HO.

摘要

获得性异位骨化 (HO) 是一种痛苦且使人虚弱的疾病，其特征是受伤后骨骼外形成骨。HO 的确切发病机制尚不清楚。在这里，我们显示 TGF-β 在小鼠中引发和促进 HO。我们发现 HO 发病后钙化软骨和新形成的骨会吸收破骨细胞，导致高水平的活性 TGF-β募集 HO 微环境中的间充质基质/祖细胞 (MSPC)。腱中的活性 TGF-β的转基因表达会自发诱导 HO，而全身性注射 TGF-β 中和抗体可减弱创伤性和 BMP 诱导的小鼠 HO 模型以及纤维性骨发育不良进展性小鼠模型中的异位骨形成。此外，MSPC 中 TGF-β 型 II 受体的诱导性敲除可抑制 HO 小鼠模型中的 HO 进展。我们的研究表明，高水平的活性 TGF-β 可作为异位骨形成的诱导剂和促进剂，并且表明 TGF-β 可能是 HO 的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab2e/5803194/87fb7f345e89/41467_2018_2988_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab2e/5803194/873ec9fc8217/41467_2018_2988_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab2e/5803194/368f8a210001/41467_2018_2988_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab2e/5803194/68d8eb4f63ca/41467_2018_2988_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab2e/5803194/68c9c9da95b4/41467_2018_2988_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab2e/5803194/99168592a1d5/41467_2018_2988_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab2e/5803194/a34c239a389f/41467_2018_2988_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab2e/5803194/87fb7f345e89/41467_2018_2988_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab2e/5803194/873ec9fc8217/41467_2018_2988_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab2e/5803194/368f8a210001/41467_2018_2988_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab2e/5803194/68d8eb4f63ca/41467_2018_2988_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab2e/5803194/68c9c9da95b4/41467_2018_2988_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab2e/5803194/99168592a1d5/41467_2018_2988_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab2e/5803194/a34c239a389f/41467_2018_2988_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab2e/5803194/87fb7f345e89/41467_2018_2988_Fig7_HTML.jpg

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