学術雑誌論文

学術雑誌論文

Bone. 2025, 194, p. 117440

RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice

Elsevier Inc.

英語

2025-05-01

https://doi.org/10.1016/j.bone.2025.117440

Kurihara T., Shimamura M., Etani Y., et al. RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice. Bone 194, 117440 (2025); https://doi.org/10.1016/j.bone.2025.117440.

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.

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100972

RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice

Elsevier Inc.

英語

2025-05-01

Bone

194

117440

https://doi.org/10.1016/j.bone.2025.117440

https://hdl.handle.net/11094/100972