Erk5 in Bone Marrow Mesenchymal Stem Cells Regulates Bone Homeostasis by Preventing Osteogenesis in Adulthood
Erk5 in Bone Marrow Mesenchymal Stem Cells Regulates Bone Homeostasis by Preventing Osteogenesis in Adulthood
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DOI：
10.1093/stmcls/sxac011
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发表时间：
2022-02-22
期刊：
影响因子：
5.2
通讯作者：
Hinoi, Eiichi
中科院分区：
文献类型：
--
作者：
Horie, Tetsuhiro;Fukasawa, Kazuya;Hinoi, Eiichi
细胞外信号调节激酶5（Erk 5）属于丝裂原活化蛋白激酶（MAPK）家族。先前，我们证明Erk 5直接磷酸化Smad特异性E3泛素蛋白连接酶2（Smurf 2）在Thr（249）（Smurf 2（Thr 249））以激活其E3泛素连接酶活性。虽然我们已经阐明了Erk 5在胚胎间充质干细胞（MSC）中对骨骼发生的重要性，但其在成人骨髓（BM）-MSC中对骨稳态的作用仍然未知。瘦素受体阳性（LepR（+））BM-MSC代表成人骨髓中骨的主要来源，并且是出生后骨稳态的关键调节剂。在这里，我们确定了BM-MSCs中的Erk 5作为成年期骨稳态的重要调节因子。在LepR（+）BM-MSCs中缺乏Erk 5的小鼠中，随着年龄的增长，骨髓组织进行性骨质增生，伴随着体内骨形成和正常骨吸收的增加。Erk 5缺陷增加BM-MSCs的成骨分化，沿着成骨分化所必需的转录因子Runx 2和Osterix的更高表达，而不影响其体外干性。Erk 5缺陷降低Smurf 2（Thr 249）磷酸化，随后增加BM-MSCs中Smad 1/5/8依赖性信号传导。Smurf 2（T249 E）突变体（一种磷酸化模拟物突变体）的遗传引入抑制了Erk 5缺陷小鼠的osteoprotein表型。这些发现表明，BM-MSCs中的Erk 5-Smurf 2（Thr 249）轴通过防止成人骨髓中的过度成骨在维持适当的骨稳态中起着关键作用。
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.