title: Novel Function of Serine Protease HTRA1 in Inhibiting Adipogenic Differentiation of Human Mesenchymal Stem Cells via MAP Kinase-Mediated MMP Upregulation.
abstract: Adipogenesis is the process by which mesenchymal stem cells (MSCs) develop into lipid-laden adipocytes. Being the dominant cell type within adipose tissue, adipocytes play a central role in regulating circulating fatty acid levels, which is considered to be of critical importance in maintaining insulin sensitivity. High temperature requirement protease A1 (HTRA1) is a newly recognized regulator of MSC differentiation, although its role as a mediator of adipogenesis has not yet been defined. The aim of this work was therefore to evaluate HTRA1's influence on human MSC (hMSC) adipogenesis and to establish a potential mode of action. We report that the addition of exogenous HTRA1 to hMSCs undergoing adipogenesis suppressed their ability to develop into lipid laden adipocytes. These effects were demonstrated as being reliant on both its protease and PDZ domain, and were mediated through the actions of c-Jun N-terminal kinase and matrix metalloproteinases (MMPs). The relevance of such findings with regards to HTRA1's potential influence on adipocyte function in vivo is made evident by the fact that HTRA1 and MMP-13 were readily identifiable within crown-like structures present in visceral adipose tissue samples from insulin resistant obese human subjects. These data therefore implicate HTRA1 as a negative regulator of MSC adipogenesis and are suggestive of its potential involvement in adipose tissue remodeling under pathological conditions. Stem Cells 2016;34:1601-1614.
authors: Bone and Stem Cell Research Group, CABMM, University of Zurich, Zurich, Switzerland.
authors: André N
authors: AN
authors: Tiaden
authors: Bone and Stem Cell Research Group, CABMM, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors: Gregor
authors: G
authors: Bahrenberg
authors: Bone and Stem Cell Research Group, CABMM, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors: Ali
authors: A
authors: Mirsaidi
authors: Bone and Stem Cell Research Group, CABMM, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors: Stephan
authors: S
authors: Glanz
authors: Department of Medicine, Dermatology and Neurology, University of Leipzig, Leipzig, Germany.|Department of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
authors: Matthias
authors: M
authors: Blüher
authors: Bone and Stem Cell Research Group, CABMM, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors: Peter J
authors: PJ
authors: Richards
mesh_terms: D050156:Adipogenesis; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D000074289:High-Temperature Requirement A Serine Peptidase 1 / Q000378:metabolism*; D006801:Humans; D050152:Intra-Abdominal Fat / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D066292:Lipid Droplets / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000201:enzymology*; D009765:Obesity / Q000473:pathology; D015854:Up-Regulation
chemical_list: D019812:Heparan Sulfate Proteoglycans; D048031:JNK Mitogen-Activated Protein Kinases; D000074289:High-Temperature Requirement A Serine Peptidase 1; D020782:Matrix Metalloproteinases
keywords: Adipogenesis; Adult stem cells; Cell signaling; Diabetes; Differentiation; HTRA1; MMP