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白细胞介素-6 通过两条不同的 BMPR1A 介导的途径增强骨形态发生蛋白-2 诱导的成骨和成脂作用。

IL-6 potentiates BMP-2-induced osteogenesis and adipogenesis via two different BMPR1A-mediated pathways.

机构信息

Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China.

Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, 200032, China.

出版信息

Cell Death Dis. 2018 Feb 2;9(2):144. doi: 10.1038/s41419-017-0126-0.

DOI:10.1038/s41419-017-0126-0
PMID:29396550
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5833364/
Abstract

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is widely used in the clinic for bone defect reconstruction because of its powerful osteoinductive capacity. However, commercially available rhBMP-2 requires a high concentration in the clinical setting for consistent bone formation. A high dose of rhBMP-2 induces a promising bone formation yield but also leads to inflammation-related events, deteriorated bone quality, and fatty tissue formation. We hypothesize that the seemingly contradictory phenomenon of coformation of new bone and excessive adipose tissue in rhBMP-2-induced bone voids may be associated with interleukin-6 (IL-6), which is significantly elevated after application of rhBMP-2/absorbable collagen sponge (rhBMP-2/ACS). Here, we show that IL-6 injection enhances new bone regeneration and induces excessive adipose tissue formation in an rhBMP-2/ACS-induced ectopic bone formation model in rats. In vitro data further show that IL-6 and its soluble receptor sIL-6R synergistically augment rhBMP-2-induced osteogenic and adipogenic differentiation of human BMSCs (hBMSCs) by promoting cell surface translocation of BMPR1A and then amplifying BMPR1A-mediated BMP/Smad and p38 MAPK pathways, respectively. Our study suggests elevated IL-6 may be responsible for coformation of new bone and excessive adipose tissue in rhBMP-2-induced bone voids.

摘要

重组人骨形态发生蛋白-2（rhBMP-2）由于其强大的成骨诱导能力，在临床上被广泛用于骨缺损重建。然而，市售的 rhBMP-2 在临床应用中需要高浓度才能保持一致的骨形成。高剂量的 rhBMP-2 虽然能诱导出有前景的骨形成效果，但也会导致炎症相关事件、骨质量恶化和脂肪组织形成。我们假设，rhBMP-2 诱导的骨腔中新骨和过多脂肪组织的形成似乎是矛盾的现象，可能与白细胞介素-6（IL-6）有关，rhBMP-2/可吸收胶原海绵（rhBMP-2/ACS）应用后 IL-6 水平显著升高。在这里，我们展示了 IL-6 注射在 rhBMP-2/ACS 诱导的异位骨形成大鼠模型中增强了新骨再生，并诱导了过多的脂肪组织形成。体外数据进一步表明，IL-6 及其可溶性受体 sIL-6R 通过促进 BMPR1A 的细胞表面易位，协同增强 rhBMP-2 诱导的人骨髓间充质干细胞（hBMSCs）成骨和成脂分化，分别放大 BMPR1A 介导的 BMP/Smad 和 p38 MAPK 途径。我们的研究表明，升高的 IL-6 可能是 rhBMP-2 诱导的骨腔中新骨和过多脂肪组织形成的原因。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/8049a36eaa6a/41419_2017_126_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/d63cc7a73282/41419_2017_126_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/871791a480b9/41419_2017_126_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/5dda84bb9927/41419_2017_126_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/095781c14f90/41419_2017_126_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/239a43a49d53/41419_2017_126_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/253e91c4d74e/41419_2017_126_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/701c2c5e0a0d/41419_2017_126_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/8049a36eaa6a/41419_2017_126_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/d63cc7a73282/41419_2017_126_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/871791a480b9/41419_2017_126_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/5dda84bb9927/41419_2017_126_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/095781c14f90/41419_2017_126_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/239a43a49d53/41419_2017_126_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/253e91c4d74e/41419_2017_126_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/701c2c5e0a0d/41419_2017_126_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cdf/5833364/8049a36eaa6a/41419_2017_126_Fig8_HTML.jpg

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