title: Synthetic triterpenoids, CDDO-Imidazolide and CDDO-Ethyl amide, induce chondrogenesis.
abstract: Novel methods for inducing chondrogenesis are critical for cartilage tissue engineering and regeneration. Here we show that the synthetic oleanane triterpenoids, CDDO-Imidazolide (CDDO-Im) and CDDO-Ethyl amide (CDDO-EA), at concentrations as low as 200 nM, induce chondrogenesis in organ cultures of newborn mouse calvaria. The cartilage phenotype was measured histologically with metachromatic toluidine blue staining for proteoglycans and by immunohistochemical staining for type II collagen. Furthermore, real-time polymerase chain reaction (PCR) analysis using mRNA from calvaria after 7-day treatment with CDDO-Im and CDDO-EA showed up-regulation of the chondrocyte markers SOX9 and type II collagen (alpha1). In addition, TGF-β; BMPs 2 and 4; Smads 3, 4, 6, and 7; and TIMPs-1 and -2 were increased. In contrast, MMP-9 was strongly down-regulated. Treatment of human bone marrow-derived mesenchymal stem cells with CDDO-Im and CDDO-EA (100 nM) induced expression of SOX9, collagen IIα1, and aggrecan, as well as BMP-2 and phospho-Smad5, confirming that the above triterpenoids induce chondrogenic differentiation. This is the first report of the use of these drugs for induction of chondrogenesis.
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States.
authors.forename: N
authors.initials: N
authors.lastname: Suh
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States.
authors.forename: S
authors.initials: S
authors.lastname: Paul
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States; Department of Food Science and Technology, Chung-Ang University, Anseong 456-756, South Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States.
authors.forename: T
authors.initials: T
authors.lastname: Yoon
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States.
authors.forename: N
authors.initials: N
authors.lastname: Shah
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States.
authors.forename: A I
authors.initials: AI
authors.lastname: Son
authors.affiliation: Department of Orthopaedic Surgery, University of California at Davis School of Medicine, Sacramento, CA 95817, United States.
authors.forename: A H
authors.initials: AH
authors.lastname: Reddi
authors.affiliation: Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, United States.
authors.forename: D
authors.initials: D
authors.lastname: Medici
authors.affiliation: Department of Pharmacology, Dartmouth Medical School, Hanover, NH 03755, United States. Electronic address: michael.sporn@dartmouth.edu.
authors.forename: M B
authors.initials: MB
authors.lastname: Sporn
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D020219:Chondrogenesis / Q000187:drug effects* / Q000502:physiology; D024043:Collagen Type II / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D009924:Organ Culture Techniques; D011509:Proteoglycans / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012886:Skull / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; C518860:2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid ethyl amide; D024043:Collagen Type II; D007093:Imidazoles; D011509:Proteoglycans; D009828:Oleanolic Acid