title: A new synthetic matrix metalloproteinase inhibitor reduces human mesenchymal stem cell adipogenesis.
abstract: Development of adipose tissue requires the differentiation of less specialized cells, such as human mesenchymal stem cells (hMSCs), into adipocytes. Since matrix metalloproteinases (MMPs) play critical roles in the cell differentiation process, we conducted investigations to determine if a novel mercaptosulfonamide-based MMP inhibitor (MMPI), YHJ-7-52, could affect hMSC adipogenic differentiation and lipid accumulation. Enzyme inhibition assays, adipogenic differentiation experiments, and quantitative PCR methods were employed to characterize this inhibitor and determine its effect upon adipogenesis. YHJ-7-52 reduced lipid accumulation in differentiated cells by comparable amounts as a potent hydroxamate MMPI, GM6001. However, YHJ-7-82, a non-inhibitory structural analog of YHJ-7-52, in which the zinc-binding thiol group is replaced by a hydroxyl group, had no effect on adipogenesis. The two MMPIs (YHJ-7-52 and GM6001) were also as effective in reducing lipid accumulation in differentiated cells as T0070907, an antagonist of peroxisome-proliferator activated receptor gamma (PPAR-gamma), at a similar concentration. PPAR-gamma is a typical adipogenic marker and a key regulatory protein for the transition of preadiopocyte to adipocyte. Moreover, MMP inhibition was able to suppress lipid accumulation in cells co-treated with Troglitazone, a PPAR-gamma agonist. Our results indicate that MMP inhibitors may be used as molecular tools for adipogenesis and obesity treatment research.
authors.affiliation: Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, United States of America.
authors.forename: Dale B
authors.initials: DB
authors.lastname: Bosco
authors.affiliation: Department of Chemistry & Biochemistry, Florida State University, Tallahassee, Florida, United States of America.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Roycik
authors.affiliation: Department of Chemistry & Biochemistry, Florida State University, Tallahassee, Florida, United States of America.
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Chemistry & Biochemistry, Florida State University, Tallahassee, Florida, United States of America.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Schwartz
authors.affiliation: Department of Chemistry & Biochemistry, Florida State University, Tallahassee, Florida, United States of America.
authors.forename: Ty J
authors.initials: TJ
authors.lastname: Lively
authors.affiliation: Department of Chemistry & Biochemistry, Florida State University, Tallahassee, Florida, United States of America.
authors.forename: Diego A R
authors.initials: DA
authors.lastname: Zorio
authors.affiliation: Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, United States of America.|Department of Chemistry & Biochemistry, Florida State University, Tallahassee, Florida, United States of America.
authors.forename: Qing-Xiang Amy
authors.identifier: http://orcid.org/0000-0001-8828-0569
authors.initials: QA
authors.lastname: Sang
mesh_terms: D050156:Adipogenesis / Q000187:drug effects*; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
chemical_list: D002839:Chromans; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D047495:PPAR gamma; D045162:Thiazolidinediones; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D000077288:Troglitazone