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

Authors
Moon, Sung-AhKim, Jin-ManLee, Young-SunCho, Han JinChoi, Young JinYoon, Jong HyukKim, DayeaChe, XiangguoJin, XianBaek, In-JeoungLee, Seung HunChoi, Je-YoungKoh, Jung-Min
Issue Date
Mar-2025
Publisher
Springer Nature
Citation
Experimental & Molecular Medicine
Journal Title
Experimental & Molecular Medicine
URI
http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/1261
DOI
10.1038/s12276-025-01419-y
ISSN
1226-3613
2092-6413
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.
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연구본부 (퇴행성 뇌질환 연구그룹)
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