Journal Article

A Stem Cell-Based Approach to Cartilage Repair

Althage, Alana, Zhu, Shoutian, Schultz, Peter G., Meeusen, Shelly, Wu, Xu, Tremblay, Matthew S., Johnson, Kristen, Payette, Joshua N., Wang, Jianing, Bouchez, Laure C., Cho, Charles Y.

2012

Overview

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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Adults / Anilides - administration & dosage / Anilides - chemistry / Anilides - pharmacology / Anilides - therapeutic use / Animal models / Animals / Arthritis / Articular / Biocompatibility / Biological and medical sciences / Biomedical materials / Breakdown / Cartilage / Cartilage, Articular - cytology / Cattle / Cell Nucleus - metabolism / Chondrocytes / Chondrocytes - cytology / Chondrocytes - drug effects / Chondrocytes - metabolism / Chondrocytes - physiology / Chondrogenesis / Collagens / Contractile Proteins - metabolism / Core Binding Factor Alpha 2 Subunit - metabolism / Core Binding Factor beta Subunit - metabolism / Disease Models, Animal / Diseases of the osteoarticular system / Effectiveness / filamin / Filamins / High-Throughput Screening Assays / Humans / Individualized Instruction / Lead / median effective concentration / Medical sciences / Mesenchymal Stromal Cells - cytology / Mesenchymal Stromal Cells - drug effects / Mesenchymal Stromal Cells - physiology / Mice / Microfilament Proteins - metabolism / Molecular biology / Molecules / Osteoarthritis / Osteoarthritis - drug therapy / Osteoarthritis - pathology / Osteoarthritis - physiopathology / Phthalic Acids - administration & dosage / Phthalic Acids - chemistry / Phthalic Acids - pharmacology / Phthalic Acids - therapeutic use / Regeneration / Small Molecule Libraries / Stem cells / Structure-Activity Relationship / therapeutics / transcription (genetics) / transcription factors / Vehicles