VGF and the VGF-derived peptide AQEE30 stimulate osteoblastic bone formation through the C3a receptor

Abstract

New therapeutic targets, especially those that stimulate bone formation in cortical bone, are needed to overcome the limitations of current antiosteoporotic drugs. We previously demonstrated that factors secreted from megakaryocytes (MKs) promote bone formation. Here we conducted a proteomic analysis to identify a novel bone-forming factor from MK secretions. We revealed that Vgf, a nerve growth factor-responsive gene, and its derived active peptide AQEE30 in MK-conditioned medium play important roles in osteoblast proliferation and in vitro bone formation. In both Vgf-deficient male and female mice, the cortical bone mass was significantly decreased due to reductions in osteoblast number and bone formation activity. AQEE30 stimulated intracellular cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity in osteoblasts, whereas an adenylyl cyclase inhibitor blocked AQEE30-stimulated osteoblast proliferation and in vitro bone formation. Complement C3a receptor-1 (C3AR1) was expressed and interacted with AQEE30 in osteoblasts, and C3AR1 inhibition blocked all AQEE30-induced changes, including stimulated proliferation, bone formation and cAMP production, in osteoblasts. Injecting mini-PEGylated AQEE30 into calvaria increased the number of osteocalcin-positive cells and new bone formation. In conclusion, this study reveals a novel role of VGF in bone formation, particularly in cortical bone, and shows that AQEE30, a VGF-derived peptide, mediates this role by activating cAMP–PKA signaling via the C3AR1 receptor in osteoblasts. Osteoporosis is a common bone disease that weakens bones and increases fracture risk. Current treatments have limitations, especially in preventing nonvertebral fractures. Researchers focused on a protein called VGF, which is known for its role in the brain but not in bone health. The study used mice and cell cultures to investigate VGF’s effects on bones. They found that VGF and its peptide AQEE30 promote bone formation by stimulating osteoblasts. They used mass spectrometry to discover that VGF is important for bone health. Mice lacking VGF had weaker bones, especially in the cortical (outer) layer. The study showed that AQEE30 works by increasing cAMP levels, a molecule that helps cells communicate and grow. This discovery suggests that targeting VGF and AQEE30 could lead to new treatments for osteoporosis. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.