title: A stem cell-based approach to cartilage repair.
abstract: Osteoarthritis (OA) is a degenerative joint disease that involves the destruction of articular cartilage and eventually leads to disability. Molecules that promote the selective differentiation of multipotent mesenchymal stem cells (MSCs) into chondrocytes may stimulate the repair of damaged cartilage. Using an image-based high-throughput screen, we identified the small molecule kartogenin, which promotes chondrocyte differentiation (median effective concentration = 100 nM), shows chondroprotective effects in vitro, and is efficacious in two OA animal models. Kartogenin binds filamin A, disrupts its interaction with the transcription factor core-binding factor β subunit (CBFβ), and induces chondrogenesis by regulating the CBFβ-RUNX1 transcriptional program. This work provides new insights into the control of chondrogenesis that may ultimately lead to a stem cell-based therapy for osteoarthritis.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA. kjohnson@gnf.org
authors.forename: Kristen
authors.initials: K
authors.lastname: Johnson
authors.forename: Shoutian
authors.initials: S
authors.lastname: Zhu
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Tremblay
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Payette
authors.forename: Jianing
authors.initials: J
authors.lastname: Wang
authors.forename: Laure C
authors.initials: LC
authors.lastname: Bouchez
authors.forename: Shelly
authors.initials: S
authors.lastname: Meeusen
authors.forename: Alana
authors.initials: A
authors.lastname: Althage
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Cho
authors.forename: Xu
authors.initials: X
authors.lastname: Wu
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
mesh_terms: D000813:Anilides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology*; D002417:Cattle; D002467:Cell Nucleus / Q000378:metabolism; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D020219:Chondrogenesis; D003285:Contractile Proteins / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D050658:Core Binding Factor beta Subunit / Q000378:metabolism; D004195:Disease Models, Animal; D064448:Filamins; D057166:High-Throughput Screening Assays; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D010003:Osteoarthritis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D010795:Phthalic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D012038:Regeneration; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D000813:Anilides; C493692:CBFB protein, human; D003285:Contractile Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; D064448:Filamins; D008840:Microfilament Proteins; D010795:Phthalic Acids; D054852:Small Molecule Libraries; C572342:kartogenin