Cellular senescence by loss of Men1 in osteoblasts is critical for age-related osteoporosis

被引：0

作者：

Ukon, Yuichiro ^{[1
]}

Kaito, Takashi ^{[1
]}

Hirai, Hiromasa ^{[1
]}

Kitahara, Takayuki ^{[1
]}

Bun, Masayuki ^{[1
]}

Kodama, Joe ^{[2
]}

Tateiwa, Daisuke ^{[3
]}

Nakagawa, Shinichi ^{[1
]}

Ikuta, Masato ^{[1
]}

Furuichi, Takuya ^{[1
]}

Kanie, Yuya ^{[1
]}

Fujimori, Takahito ^{[1
]}

Takenaka, Shota ^{[1
]}

Yamamuro, Tadashi ^{[4
,5
]}

Otsuru, Satoru ^{[2
]}

Okada, Seiji ^{[1
]}

Yamashita, Masakatsu ^{[6
]}

Imamura, Takeshi ^{[7
]}

机构：

[1] Osaka Univ, Grad Sch Med, Dept Orthopaed Surg, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan

[2] Univ Maryland, Sch Med, Dept Orthoped, Baltimore, MD USA

[3] Osaka Gen Med Ctr, Dept Orthopaed Surg, Osaka, Japan

[4] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA USA

[5] Harvard Med Sch, Boston, MA USA

[6] Ehime Univ, Grad Sch Med, Dept Immunol, Toon, Ehime, Japan

[7] Ehime Univ, Grad Sch Med, Dept Mol Med Pathogenesis, Toon, Ehime, Japan

来源：

AGING CELL | 2024年

关键词：

AMPK; cellular senescence; Men1; mTORC1; osteoporosis; LIFE-SPAN; LONG BONES; CELLS; TUMORS; MICE;

D O I：

10.1111/acel.14254

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Recent evidence suggests an association between age-related osteoporosis and cellular senescence in the bone; however, the specific bone cells that play a critical role in age-related osteoporosis and the mechanism remain unknown. Results revealed that age-related osteoporosis is characterized by the loss of osteoblast Men1. Osteoblast-specific inducible knockout of Men1 caused structural changes in the mice bones, matching the phenotypes in patients with age-related osteoporosis. Histomorphometrically, Men1-knockout mice femurs decreased osteoblastic activity and increased osteoclastic activity, hallmarks of age-related osteoporosis. Loss of Men1 induces cellular senescence via mTORC1 activation and AMPK suppression, rescued by metformin treatment. In bone morphogenetic protein-indued bone model, loss of Men1 leads to accumulation of senescent cells and osteoporotic bone formation, which are ameliorated by metformin. Our results indicate that cellular senescence in osteoblasts plays a critical role in age-related osteoporosis and that osteoblast-specific inducible Men1-knockout mice offer a promising model for developing therapeutics for age-related osteoporosis.

引用

页数：17

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