Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a β-catenin-dependent mechanism.
Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a β-catenin-dependent mechanism.
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DOI：
10.1016/j.bone.2011.08.010
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发表时间：
2012-02
期刊：
影响因子：
4.1
通讯作者：
MacDougald OA
中科院分区：
文献类型：
--
作者：
Cawthorn WP;Bree AJ;Yao Y;Du B;Hemati N;Martinez-Santibañez G;MacDougald OA
Wnt 10 b是间充质干细胞（MSC）命运的既定调节因子，其抑制脂肪生成并刺激成骨细胞生成，从而影响体内骨量。然而，Wnt 10 b发挥这些作用的下游机制知之甚少。此外，其他内源性Wnt配体是否也调节MSC命运仍有待充分解决。在这项研究中，我们确定Wnt 6和Wnt 10 a作为额外的Wnt家族成员，像Wnt 10 b一样，在体内和体外白色脂肪细胞发育过程中下调，这表明Wnt 6和/或Wnt 10 a也可能抑制脂肪形成。为了评估Wnt 6、Wnt 10a和Wnt 10 b调节间充质细胞命运的相对活性，我们在双能ST 2细胞和3 T3-L1前脂肪细胞中使用了功能获得和功能丧失方法。Wnt 10a的增强表达稳定β-连环蛋白，抑制脂肪生成并刺激成骨细胞生成，其程度与Wnt 10 b相似，而Wnt 6的稳定表达对这些过程的影响弱于Wnt 10a或Wnt 10 b。相反，内源性Wnt 6的敲除与更大的前脂肪细胞分化和受损的成骨细胞比敲除Wnt 10a或Wnt 10 b，这表明，在这些Wnt配体，Wnt 6是最有效的MSC命运的内源性调节剂。最后，我们发现β-连环蛋白的敲低完全阻止了Wnt 6、Wnt 10a或Wnt 10 b对脂肪形成的抑制和对成骨细胞分化的刺激。还研究了Wnt调节β-连环蛋白下游MSC命运的潜在机制。总之，这项研究确定了Wnt 10a和Wnt 6作为MSC命运的额外调节因子，并证明了Wnt 6，Wnt 10a和Wnt 10 b影响间充质前体分化所需的β-连环蛋白下游机制。
Wnt10b is an established regulator of mesenchymal stem cell (MSC) fate that inhibits adipogenesis and stimulates osteoblastogenesis, thereby impacting bone mass in vivo. However, downstream mechanisms through which Wnt10b exerts these effects are poorly understood. Moreover, whether other endogenous Wnt ligands also modulate MSC fate remains to be fully addressed. In this study, we identify Wnt6 and Wnt10a as additional Wnt family members that, like Wnt10b, are downregulated during development of white adipocytes in vivo and in vitro, suggesting that Wnt6 and/or Wnt10a may also inhibit adipogenesis. To assess the relative activities of Wnt6, Wnt10a and Wnt10b to regulate mesenchymal cell fate, we used gain- and loss-of function approaches in bipotential ST2 cells and in 3T3-L1 preadipocytes. Enforced expression of Wnt10a stabilizes β-catenin, suppresses adipogenesis and stimulates osteoblastogenesis to a similar extent as Wnt10b, whereas stable expression of Wnt6 has a weaker effect on these processes than Wnt10a or Wnt10b. In contrast, knockdown of endogenous Wnt6 is associated with greater preadipocyte differentiation and impaired osteoblastogenesis than knockdown of Wnt10a or Wnt10b, suggesting that, amongst these Wnt ligands, Wnt6 is the most potent endogenous regulator of MSC fate. Finally, we show that knockdown of β-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by Wnt6, Wnt10a or Wnt10b. Potential mechanisms whereby Wnts regulate fate of MSCs downstream of β-catenin are also investigated. In conclusion, this study identifies Wnt10a and Wnt6 as additional regulators of MSC fate and demonstrates that mechanisms downstream of β-catenin are required for Wnt6, Wnt10a and Wnt10b to influence differentiation of mesenchymal precursors.
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影响因子：
5.3
作者：
Kang, S;Bajnok, L;MacDougald, OA
通讯作者：
MacDougald, OA
DOI：
10.1016/j.bbrc.2005.03.007
发表时间：
2005-05-06
影响因子：
3.1
作者：
Kanazawa, A;Tsukada, S;Maeda, S
通讯作者：
Maeda, S
影响因子：
11.8
作者：
Bialek, P;Kern, B;Karsenty, G
通讯作者：
Karsenty, G
影响因子：
4.8
作者：
Erickson, RL;Hemati, N;MacDougald, OA
通讯作者：
MacDougald, OA
影响因子：
7.7
作者：
Lagathu, Claire;Christodoulides, Constantinos;Virtue, Sam;Cawthorn, William P.;Franzin, Chiara;Kimber, Wendy A.;Nora, Edoardo Dalla;Campbell, Mark;Medina-Gomez, Gema;Cheyette, Benjamin N. R.;Vidal-Puig, Antonio J.;Sethi, Jaswinder K.
通讯作者：
Sethi, Jaswinder K.