Reference - Detail
| RRC ID | 83881 |
|---|---|
| Author | Kurihara T, Shimamura M, Etani Y, Noguchi T, Fukuda Y, Ochiai N, Goshima A, Miura T, Hirao M, Sugimoto A, Ju N, Yamakawa S, Kanamoto T, Nakata K, Okada S, Ebina K. |
| Title | RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice. |
| Journal | Bone |
| Abstract |
PURPOSE:Estrogen deficiency following menopause increases receptor activator of nuclear factor-kappa B ligand (RANKL) expression in osteoblasts, thereby promoting osteoclast differentiation, and enhances T cell-derived tumor necrosis factor-alpha (TNFα) production, which induces sclerostin expression in osteocytes, thereby inhibiting bone formation. This study aimed to develop a novel uncoupling therapeutic agent for osteoporosis. METHODS:We developed microglial healing peptide 1 with N-terminal acetylation and C-terminal amidation (MHP1-AcN), a modified RANKL peptide with N-terminal acetylation and C-terminal amidation lacking the osteoclast activating CD loop. Given the structural similarities of RANK and TNF receptor 1 (TNFR1), we hypothesized that MHP1-AcN could inhibit both the RANKL-RANK and TNFα-TNFR1 pathways to address the pathophysiology of osteoporosis, as evaluated in vitro and in vivo using an ovariectomized mouse model. RESULTS:In ovariectomized mice, MHP1-AcN inhibited osteoclastogenesis, reduced osteocytic sclerostin expression, prevented bone loss, and improved the femoral cancellous and cortical bone microarchitecture. Unlike anti-RANKL antibody, MHP1-AcN considerably preserved bone formation by osteoblasts and enhanced bone strength, as evidenced by increases in energy absorption capacity. In vitro, MHP1-AcN bound to both RANK and TNFR1, suppressing osteoclast activity via the RANKL-RANK pathway and reducing sclerostin expression through the TNFα-TNFR1-nuclear factor-kappa B pathway. MHP1-AcN did not affect osteoblast proliferation and differentiation or RANKL expression. CONCLUSION:MHP1-AcN effectively inhibits osteoclastogenesis and sclerostin-mediated suppression of bone formation while considerably preserving osteoblast function. These findings suggest that MHP1-AcN, which targets dual pathways critical for bone homeostasis, is a promising uncoupling therapeutic agent for osteoporosis. |
| Volume | 194 |
| Pages | 117440 |
| Published | 2025-5-1 |
| DOI | 10.1016/j.bone.2025.117440 |
| PII | S8756-3282(25)00052-3 |
| PMID | 40032017 |
| MeSH | Adaptor Proteins, Signal Transducing / metabolism Animals Cell Differentiation / drug effects Female Mice Mice, Inbred C57BL Osteoblasts / drug effects Osteoblasts / metabolism Osteoclasts / drug effects Osteoclasts / metabolism Osteogenesis* / drug effects Osteoporosis* / drug therapy Osteoporosis* / metabolism Osteoporosis* / pathology Ovariectomy* Peptides / chemistry Peptides / pharmacology RANK Ligand* / metabolism Receptor Activator of Nuclear Factor-kappa B* / metabolism Receptors, Tumor Necrosis Factor, Type I* / metabolism |
| IF | 4.147 |
| Resource | |
| Human and Animal Cells | MC3T3-E1(RCB1126) Saos-2(RCB0428) |