Bone · 2025
RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Kurihara Takuya, Shimamura Munehisa, Etani Yuki, Noguchi Takaaki, Fukuda Yuji, Ochiai Nagahiro, Goshima Atsushi, Miura Taihei, Hirao Makoto, Sugimoto Atsushi, Ju Nan, Yamakawa Satoshi, Kanamoto Takashi, Nakata Ken, Okada Seiji, Ebina Kosuke
Аннотация
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.
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.
Предметные рубрики MeSH
AnimalsOvariectomyFemaleOsteoporosisRANK LigandReceptors, Tumor Necrosis Factor, Type IPeptidesMiceOsteogenesisReceptor Activator of Nuclear Factor-kappa BMice, Inbred C57BLOsteoclastsOsteoblastsAdaptor Proteins, Signal TransducingCell DifferentiationTumor Necrosis Factor-alphaSignal TransductionOsteocytes