Major vault protein (MVP) negatively regulates osteoclastogenesis via calcineurin-NFATc1 pathway inhibition.
Major vault protein (MVP) negatively regulates osteoclastogenesis via calcineurin-NFATc1 pathway inhibition.
复制标题
主要穹窿蛋白 (MVP) 通过抑制钙调神经磷酸酶-NFATc1 通路负向调节破骨细胞生成
作者：
Yuan L;Zhao N;Wang J;Liu Y;Meng L;Guo S;Wiemer EAC;Chen Q;Mao Y;Ben J;Ma J
原理：通过成骨细胞和破骨细胞之间的平衡相互作用来维持骨内环境的稳定。破骨细胞来源于单核/巨噬细胞系。已知主要vault蛋白(MVP)可促进巨噬细胞的凋亡和预防代谢性疾病。然而，MVP是否参与破骨细胞的形成尚不清楚。在这里，我们确定了MVP作为破骨细胞生成的负性调节因子的一个重要功能以及它在预防骨丢失方面的治疗潜力。方法：采用免疫组织化学方法检测MVP在人肿瘤组织中的表达。接下来，我们建立了全身(MVP-/-)和单核细胞特异性(Mvpf/fLyz2-Cre)MVP基因敲除小鼠，利用显微CT和骨组织形态计量学观察MVP基因敲除小鼠的骨表型和破骨细胞的形成。此外，我们还观察了MVP在体外对破骨细胞分化、骨吸收、NFATc1激活和钙振荡的影响。最后，我们探索了在两种骨质疏松症小鼠模型中靶向MVP的临床潜力，并使用腺相关病毒(AAV)基因在小鼠体内局部过表达MVP。结果：我们发现MVP-/-和Mvpf/fLyz2-Cre小鼠都表现出骨质疏松症样表型。MVP缺乏也增强了钙调神经磷酸酶-NFATc1信号，促进了NFATc1活性，从而促进了破骨细胞的形成和骨吸收。小分子抑制剂FK506抑制钙调神经磷酸酶可纠正Mvpf/fLyz2-Cre组促进的破骨细胞生成。此外，Mvpf/fLyz2-Cre组MVP的重新表达挽救了钙调神经磷酸酶的表达。野生型小鼠过表达MVP可防止去卵巢(OVX)和邻近头盖骨的脂多糖(LPS)注射小鼠模型的病理性骨丢失。结论：MVP通过抑制钙调神经磷酸酶-NFATc1信号通路负向调节破骨细胞分化和骨吸收。在破骨细胞相关的骨疾病中，如骨质疏松，对MVP活性的操纵可能是一个有吸引力的治疗靶点。
Rationale: Bone homeostasis is maintained by a balanced interplay of osteoblasts and osteoclasts. Osteoclasts are derived from monocyte/macrophage lineage. Major vault protein (MVP) is known to promote apoptosis and prevent metabolic diseases in macrophage. However, whether MVP is involved in osteoclastogenesis is unknown. Here, we identified an important function of MVP as a negative regulator of osteoclastogenesis and its therapeutic potential in preventing bone loss. Methods: Expression of MVP in osteoclasts was investigated in human tumor tissues with immunohistochemical staining. Next, we generated total body (Mvp-/-) and monocyte-specific (Mvpf/fLyz2-Cre) MVP gene knockout mice to observe bone phenotype and osteoclastogenesis using micro-CT and bone histomorphometry. Moreover, we examined the effects of MVP on osteoclast differentiation, bone resorption, NFATc1 activation and calcium oscillations in vitro. Finally, we explored the clinical potential of targeting MVP in two osteoporosis mouse models and used an adeno-associated virus (AAV) gene to overexpress MVP locally in mice. Results: We found that Mvp-/- and Mvpf/fLyz2-Cre mice both exhibited osteoporosis-like phenotypes. MVP-deficiency also enhanced calcineurin-NFATc1 signaling and promoted NFATc1 activity, which led to enhanced osteoclastogenesis and bone resorption. Calcineurin inhibition using the small molecule inhibitor FK506 corrected the enhanced osteoclastogenesis in Mvpf/fLyz2-Cre group. Additionally, MVP reexpression in Mvpf/fLyz2-Cre group rescued calcineurin expression. MVP overexpression in wild-type mice prevented pathologic bone loss in mouse models of ovariectomized (OVX) and calvaria-adjacent lipopolysaccharide (LPS)-injected. Conclusions: Our data suggested that MVP negatively regulates osteoclast differentiation and bone resorption via inhibition of calcineurin-NFATc1 signaling. In osteoclast-related bone diseases such as osteoporosis, manipulation of MVP activity may be an attractive therapeutic target.
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影响因子：
6.7
作者：
Dortet L;Mostowy S;Samba-Louaka A;Gouin E;Nahori MA;Wiemer EA;Dussurget O;Cossart P
通讯作者：
Cossart P
影响因子：
15.3
作者：
Asagiri, M;Sato, K;Takayanagi, H
通讯作者：
Takayanagi, H
影响因子：
3.8
作者：
Esfandiary, Reza;Kickhoefer, Valerie A.;Middaugh, C. Russell
通讯作者：
Middaugh, C. Russell
DOI：
10.1056/nejmp1202623
发表时间：
2012-05-31
期刊：
The New England journal of medicine
影响因子：
--
作者：
Black DM;Bauer DC;Schwartz AV;Cummings SR;Rosen CJ
通讯作者：
Rosen CJ
GATA4 作为一种新型调节因子，通过 Barx1 参与神经嵴和颅面骨骼的发育。
影响因子：
12.4
作者：
Guo S;Zhang Y;Zhou T;Wang D;Weng Y;Chen Q;Ma J;Li YP;Wang L
通讯作者：
Wang L