Erk5 in Bone Marrow Mesenchymal Stem Cells Regulates Bone Homeostasis by Preventing Osteogenesis in Adulthood

被引：16

作者：

Horie, Tetsuhiro ^{[1
]}

Fukasawa, Kazuya ^{[1
]}

Yamada, Takanori ^{[1
]}

Mizuno, Seiya ^{[2
]}

Iezaki, Takashi ^{[1
]}

Tokumura, Kazuya ^{[1
]}

Iwahashi, Sayuki ^{[1
]}

Sakai, Shiho ^{[1
]}

Suzuki, Akane ^{[1
]}

Kubo, Takuya ^{[1
]}

Osumi, Ryoma ^{[1
]}

Tomizawa, Akane ^{[1
]}

Ochi, Hiroki ^{[3
]}

Sato, Shingo ^{[4
]}

Kaneda, Katsuyuki ^{[5
]}

Takahashi, Satoru ^{[2
]}

Hinoi, Eiichi ^{[1
,6
]}

机构：

[1] Gifu Pharmaceut Univ, Dept Bioact Mol, Pharmacol, Gifu 5011196, Japan

[2] Univ Tsukuba, Lab Anim Resource Ctr, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

[3] Natl Rehabil Ctr Persons Disabil, Res Inst, Dept Rehabil Motor Funct, Tokorozawa, Saitama, Japan

[4] Tokyo Med & Dent Univ, Ctr Innovat Canc Treatment, Tokyo, Japan

[5] Kanazawa Univ, Div Pharmaceut Sci, Lab Mol Pharmacol, Grad Sch, Kanazawa, Ishikawa, Japan

[6] Gifu Univ, United Grad Sch Drug Discovery & Med Informat Sci, Gifu, Japan

来源：

STEM CELLS | 2022年 / 40卷 / 04期

基金：

日本学术振兴会;

关键词：

bone marrow mesenchymal stem cells; extracellular signal-regulated kinase 5; Smad specific E3 ubiquitin protein ligase 2; bone homeostasis; osteogenesis; CRE RECOMBINASE; STROMAL CELLS; LEPTIN; EXPRESSION; MICE; DRIVEN; NICHE;

D O I：

10.1093/stmcls/sxac011

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Extracellular signal-regulated kinase 5 (Erk5) belongs to the mitogen-activated protein kinase (MAPK) family. Previously, we demonstrated that Erk5 directly phosphorylates Smad-specific E3 ubiquitin protein ligase 2 (Smurf2) at Thr(249) (Smurf2(Thr249)) to activate its E3 ubiquitin ligase activity. Although we have clarified the importance of Erk5 in embryonic mesenchymal stem cells (MSCs) on skeletogenesis, its role in adult bone marrow (BM)-MSCs on bone homeostasis remains unknown. Leptin receptor-positive (LepR(+)) BM-MSCs represent a major source of bone in adult bone marrow and are critical regulators of postnatal bone homeostasis. Here, we identified Erk5 in BM-MSCs as an important regulator of bone homeostasis in adulthood. Bone marrow tissue was progressively osteosclerotic in mice lacking Erk5 in LepR(+) BM-MSCs with age, accompanied by increased bone formation and normal bone resorption in vivo. Erk5 deficiency increased the osteogenic differentiation of BM-MSCs along with a higher expression of Runx2 and Osterix, essential transcription factors for osteogenic differentiation, without affecting their stemness in vitro. Erk5 deficiency decreased Smurf2(Thr249) phosphorylation and subsequently increased Smad1/5/8-dependent signaling in BM-MSCs. The genetic introduction of the Smurf2(T249E) mutant (a phosphomimetic mutant) suppressed the osteosclerotic phenotype in Erk5-deficient mice. These findings suggest that the Erk5-Smurf2(Thr249) axis in BM-MSCs plays a critical role in the maintenance of proper bone homeostasis by preventing excessive osteogenesis in adult bone marrow.

引用

页码：411 / 422

页数：12

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