Megakaryocytes promote bone formation through coupling osteogenesis with angiogenesis by secreting TGF-β1
Megakaryocytes promote bone formation through coupling osteogenesis with angiogenesis by secreting TGF-β1
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DOI：
10.7150/thno.40559
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发表时间：
2020-01
期刊：
影响因子：
12.4
通讯作者：
Yong Tang;Mengjia Hu;Yang Xu;Fang Chen;Shilei Chen;Mo Chen;Y. Qi;M. Shen;Cheng Wang;Yukai Lu;Zihao Zhang;Haotao Zeng;Yong Quan;Fengchao Wang;Yong-ping Su;D. Zeng;Song Wang;Junping Wang
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文献类型：
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作者：
Yong Tang;Mengjia Hu;Yang Xu;Fang Chen;Shilei Chen;Mo Chen;Y. Qi;M. Shen;Cheng Wang;Yukai Lu;Zihao Zhang;Haotao Zeng;Yong Quan;Fengchao Wang;Yong-ping Su;D. Zeng;Song Wang;Junping Wang
基本原理：造血系统与骨骼系统关系密切，巨核细胞可能参与维持骨稳态。然而，在稳态和应力条件下，MK在骨形成中的确切作用和潜在机制仍不清楚。方法：我们首先使用c-Mpl缺陷小鼠和MKs条件性缺失小鼠评估骨髓中MKs缺陷的骨表型。观察成骨细胞增殖、分化及CD 31 hiEmcnhi管形成情况。通过RNA测序和酶联免疫吸附试验（ELISA）检测MKs中骨形成相关生长因子的表达。用特异性去除MKs中TGF-β1的小鼠进一步验证MKs对成骨和血管生成的影响。最后，在小鼠模型中测试辐射诱导的骨损伤的MK治疗。结果：我们发现MKs缺乏明显损害骨形成。进一步的研究表明，MK可通过分泌高水平的TGF-β1促进OB增殖和分化，以及CD 31 hiEmcnhi血管的形成。与这些发现一致，MK中TGF-β1特异性耗竭的小鼠显示骨量和强度显著降低。重要的是，MK或血小板生成素（TPO）治疗通过直接或间接增加骨髓中TGF-β1的水平，显著减轻了小鼠的放射性骨损伤。MKS源性TGF-β1也参与了辐射后OB细胞凋亡的抑制和DNA损伤修复。结论：我们的研究结果表明，MK通过分泌TGF-β1促进骨形成，这可能为治疗放射性骨质疏松症提供了一种潜在的治疗策略。
Rationale: The hematopoietic system and skeletal system have a close relationship, and megakaryocytes (MKs) may be involved in maintaining bone homeostasis. However, the exact role and underlying mechanism of MKs in bone formation during steady-state and stress conditions are still unclear. Methods: We first evaluated the bone phenotype with MKs deficiency in bone marrow by using c-Mpl-deficient mice and MKs-conditionally deleted mice. Then, osteoblasts (OBs) proliferation and differentiation and CD31hiEmcnhi tube formation were assessed. The expression of growth factors related to bone formation in MKs was detected by RNA-sequencing and enzyme-linked immunosorbent assays (ELISAs). Mice with specific depletion of TGF-β1 in MKs were used to further verify the effect of MKs on osteogenesis and angiogenesis. Finally, MKs treatment of irradiation-induced bone injury was tested in a mouse model. Results: We found that MKs deficiency significantly impaired bone formation. Further investigations revealed that MKs could promote OBs proliferation and differentiation, as well as CD31hiEmcnhi vessels formation, by secreting high levels of TGF-β1. Consistent with these findings, mice with specific depletion of TGF-β1 in MKs displayed significantly decreased bone mass and strength. Importantly, treatment with MKs or thrombopoietin (TPO) substantially attenuated radioactive bone injury in mice by directly or indirectly increasing the level of TGF-β1 in bone marrow. MKs-derived TGF-β1 was also involved in suppressing apoptosis and promoting DNA damage repair in OBs after irradiation exposure. Conclusions: Our findings demonstrate that MKs contribute to bone formation through coupling osteogenesis with angiogenesis by secreting TGF-β1, which may offer a potential therapeutic strategy for the treatment of irradiation-induced osteoporosis.