A specific bone vessel subtype, strongly positive for CD31 and endomucin (CD31hiEmcnhi), is identified as coupling angiogenesis and osteogenesis. The abundance of type CD31hiEmcnhi vessels decrease during ageing. Here we show that expression of the miR-497â¼195 cluster is high in CD31hiEmcnhi endothelium but gradually decreases during ageing. Mice with depletion of miR-497â¼195 in endothelial cells show fewer CD31hiEmcnhi vessels and lower bone mass. Conversely, transgenic overexpression of miR-497â¼195 in murine endothelium alleviates age-related reduction of type CD31hiEmcnhi vessels and bone loss. miR-497â¼195 cluster maintains the endothelial Notch activity and HIF-1α stability via targeting F-box and WD-40 domain protein (Fbxw7) and Prolyl 4-hydroxylase possessing a transmembrane domain (P4HTM) respectively. Notably, endothelialium-specific activation of miR-195 by intravenous injection of aptamer-agomiR-195 stimulates CD31hiEmcnhi vessel and bone formation in aged mice. Together, our study indicates that miR-497â¼195 regulates angiogenesis coupled with osteogenesis and may represent a potential therapeutic target for age-related osteoporosis.
Hypoxia-Inducible Factor 1, alpha Subunit/genetics , MicroRNAs/genetics , Osteoporosis/therapy , Platelet Endothelial Cell Adhesion Molecule-1/genetics , Receptor, Notch1/genetics , Sialoglycoproteins/genetics , Animals , Antagomirs/genetics , Antagomirs/metabolism , Aptamers, Nucleotide/genetics , Aptamers, Nucleotide/metabolism , Bone Density , Bone and Bones/blood supply , Bone and Bones/metabolism , Bone and Bones/pathology , F-Box-WD Repeat-Containing Protein 7/genetics , F-Box-WD Repeat-Containing Protein 7/metabolism , Gene Expression Regulation, Developmental , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Mice , Mice, Knockout , MicroRNAs/agonists , MicroRNAs/antagonists & inhibitors , MicroRNAs/metabolism , Molecular Targeted Therapy , Neovascularization, Physiologic/genetics , Osteogenesis/genetics , Osteoporosis/genetics , Osteoporosis/metabolism , Osteoporosis/pathology , Platelet Endothelial Cell Adhesion Molecule-1/agonists , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Prolyl Hydroxylases/genetics , Prolyl Hydroxylases/metabolism , Receptor, Notch1/metabolism , Sialoglycoproteins/agonists , Sialoglycoproteins/metabolism , Signal Transduction
Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-ß superfamily. Recent studies confirmed that GDF11 plays an important role in regulating the regeneration of brain, skeletal muscle, and heart during aging; however, its role in bone metabolism remains unclear. Thus, the aim of this study was to determine the effects of GDF11 on bone metabolism, including bone formation and bone resorption, both in vitro and in vivo. Our results showed that GDF11 inhibited osteoblastic differentiation of bone marrow mesenchymal stem cells in vitro. Mechanistically, GDF11 repressed Runx2 expression by inducing SMAD2/3 phosphorylation during osteoblast differentiation. Moreover, intraperitoneal injection of GDF11 inhibited bone formation and accelerated age-related bone loss in mice. Our results also showed that GDF11 had no effect on osteoclast differentiation or bone resorption both in vitro and in vivo. These results provide a further rationale for the therapeutic targeting of GDF11 for the treatment of age-related osteoporosis.
Bone Marrow Cells/metabolism , Bone Morphogenetic Proteins/metabolism , Bone Resorption/metabolism , Growth Differentiation Factors/metabolism , Mesenchymal Stem Cells/metabolism , Osteogenesis/physiology , Animals , Bone Morphogenetic Proteins/pharmacology , Cell Differentiation/physiology , Female , Growth Differentiation Factors/pharmacology , Mice , Mice, Inbred C57BL , Osteogenesis/drug effects , Smad2 Protein/metabolism , Smad3 Protein/metabolism
