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Original Articles

MAPK signaling has stage-dependent osteogenic effects on human adipose-derived stem cells in vitro

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Pages 129-146 | Received 26 May 2016, Accepted 14 Mar 2017, Published online: 19 May 2017
 

ABSTRACT

Overview: The use of pro-osteogenic growth factors, such as BMP2, in human adipose-derived stem cell (ASC) osteogenesis is well described. Because these growth factors work via signal transduction pathways, such as the mitogen-activated protein kinase (MAPK) cascade, a study of the relationship between MAPK signaling and ASC osteogenesis was conducted. Materials and Methods: ERK, JNK, and p38MAPK activation were measured in ASCs osteo-induced using either dexamethasone or vitamin D3 and correlated with mineralization. Activation and mineralization were also measured without dexamethasone or using the glucocorticoid, cortisone. The expression of the MAPK phosphatase, MKP1, and its relationship to mineralization was also assessed. The effect of decreasing MAPK activation on mineralization through the use of exogenous inhibitors was examined along with siRNA-knockdown and adenoviral overexpression of ERK1/2. Finally, the effect of ERK1/2 overexpression on ASCs induced on PLGA scaffolds was assessed. Results: ASC mineralization in dexamethasone or vitamin D3-induced ASCs correlated with both increased ERK1/2 and JNK1/2 activation. ASCs induced without dexamethasone also mineralized, with JNK1/2 signaling possibly mediating this event. No link between cortisone induction and MAPK signaling could be ascertained. ASCs treated with ERK, JNK, or p38MAPK inhibitors showed decreased osteogenic gene expression and diminished mineralization. Mineralization levels were also affected by viruses designed to inhibit or augment ERK1/2 expression and activity. Finally, ASC mineralization appeared to be a balance between the MAPK kinase activity and MKP1. Conclusions: It is likely that MAPK signaling plays a significant role in ASC osteogenesis, affecting differentiation in kinase- and stage-specific manners.

Acknowledgments

The authors thank the following UCLA core facilities: the UCLA Genotyping and Sequencing Core for their sequencing of our MAPK constructs and the UCLA Vectorcore for the cloning, amplification, and titration of the recombinant adenoviruses used in this study.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

Funding

This study was supported in part by a National Institutes of Health grant (NIDCR R01DE018931; PI: Zuk, P) and a Thrasher Family Foundation grant (PI: Zuk, P). The UCLA Vectorcore is supported by the UCLA Jonsson Comprehensive Cancer Center (JCCC), under a P30 grant (CA016042) and the UCLA CURE: Digestive Diseases Research Center under P30 grant (DK041301).

Supplemental data

Supplemental files referred to in this article can be accessed on the publisher’s website.

Additional information

Funding

This study was supported in part by a National Institutes of Health grant (NIDCR R01DE018931; PI: Zuk, P) and a Thrasher Family Foundation grant (PI: Zuk, P). The UCLA Vectorcore is supported by the UCLA Jonsson Comprehensive Cancer Center (JCCC), under a P30 grant (CA016042) and the UCLA CURE: Digestive Diseases Research Center under P30 grant (DK041301).

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