Departments of Orthopaedic Surgery and Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, 10117, Germany.
Commun Biol. 2024 Mar 13;7(1):315. doi: 10.1038/s42003-024-05915-1.
Skeletal development depends on coordinated angiogenesis and osteogenesis. Bone morphogenetic proteins direct bone formation in part by activating SMAD1/5 signaling in osteoblasts. However, the role of SMAD1/5 in skeletal endothelium is unknown. Here, we found that endothelial cell-conditional SMAD1/5 depletion in juvenile mice caused metaphyseal and diaphyseal hypervascularity, resulting in altered trabecular and cortical bone formation. SMAD1/5 depletion induced excessive sprouting and disrupting the morphology of the metaphyseal vessels, with impaired anastomotic loop formation at the chondro-osseous junction. Endothelial SMAD1/5 depletion impaired growth plate resorption and, upon long-term depletion, abrogated osteoprogenitor recruitment to the primary spongiosa. Finally, in the diaphysis, endothelial SMAD1/5 activity was necessary to maintain the sinusoidal phenotype, with SMAD1/5 depletion inducing formation of large vascular loops and elevated vascular permeability. Together, endothelial SMAD1/5 activity sustains skeletal vascular morphogenesis and function and coordinates growth plate remodeling and osteoprogenitor recruitment dynamics in juvenile mouse bone.
骨骼发育依赖于血管生成和骨生成的协调。骨形态发生蛋白通过在成骨细胞中激活 SMAD1/5 信号传导来指导骨形成。然而，SMAD1/5 在骨骼内皮细胞中的作用尚不清楚。在这里，我们发现幼年小鼠骨骼内皮细胞条件性 SMAD1/5 缺失会导致干骺端和骨干的血管过度生长，导致骨小梁和皮质骨形成发生改变。SMAD1/5 缺失诱导过度发芽并破坏干骺端血管的形态，在软骨-骨交界处的吻合环形成受损。内皮细胞 SMAD1/5 缺失会损害生长板的吸收，并且在长期缺失的情况下，会阻止前成骨细胞招募到初级松质骨。最后，在骨干中，内皮细胞 SMAD1/5 的活性对于维持窦状表型是必需的，SMAD1/5 缺失会诱导大血管环的形成和血管通透性的升高。总之，内皮细胞 SMAD1/5 的活性维持骨骼血管形态发生和功能，并协调幼年小鼠骨骼中生长板重塑和前成骨细胞募集的动力学。
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