A Stem Cell–Based Approach to Cartilage Repair

Osteoarthritis and Kartogenin Osteoarthritis is characterized by progressive breakdown of articular cartilage and affects over 25 million people in the United States. Mesenchymal stem cells (MSCs), which reside in healthy and diseased joints, are multipotent adult stem cells that are able to differentiate into a variety of cell types. Johnson et al. (p. 717, published online 5 April) identified a small molecule, kartogenin, which was able to induce MSCs to differentiate into chondrocytes in vitro. When administered locally, kartogenin was efficacious in two animal models of osteoarthritis. A chemical screen using mesenchymal stem cells identifies a small molecule, kartogenin, that can promote chondrogenesis. 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.

[1]  P. Schultz,et al.  A small molecule accelerates neuronal differentiation in the adult rat , 2010, Proceedings of the National Academy of Sciences.

[2]  Ericka Stricklin-Parker,et al.  Ann , 2005 .

[3]  David J. Hunter,et al.  Pharmacologic therapy for osteoarthritis—the era of disease modification , 2011, Nature Reviews Rheumatology.

[4]  J. Reginster,et al.  Introduction and WHO perspective on the global burden of musculoskeletal conditions. , 2002, Rheumatology.

[5]  Y. Wang,et al.  A 90 kDa fragment of filamin A promotes Casodex-induced growth inhibition in Casodex-resistant androgen receptor positive C4-2 prostate cancer cells , 2007, Oncogene.

[6]  Kozo Nakamura,et al.  Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. , 2006, Arthritis and rheumatism.

[7]  S. Koelling,et al.  Migratory chondrogenic progenitor cells from repair tissue during the later stages of human osteoarthritis. , 2009, Cell stem cell.

[8]  S. Shapiro,et al.  Filamin A-Bound PEBP2β/CBFβ Is Retained in the Cytoplasm and Prevented from Functioning as a Partner of the Runx1 Transcription Factor , 2005, Molecular and Cellular Biology.

[9]  P. Schultz,et al.  A small molecule primes embryonic stem cells for differentiation. , 2009, Cell stem cell.

[10]  J H Hartwig,et al.  Human endothelial actin-binding protein (ABP-280, nonmuscle filamin): a molecular leaf spring , 1990, The Journal of cell biology.

[11]  D. Levanon,et al.  Structure and regulated expression of mammalian RUNX genes , 2004, Oncogene.

[12]  W. B. van den Berg,et al.  Development of osteoarthritic lesions in mice by "metabolic" and "mechanical" alterations in the knee joints. , 1989, The American journal of pathology.

[13]  A. Dray,et al.  Osteoarthritic pain: a review of current, theoretical and emerging therapeutics , 2008, Expert opinion on investigational drugs.

[14]  Makoto Sato,et al.  Targeted Disruption of Cbfa1 Results in a Complete Lack of Bone Formation owing to Maturational Arrest of Osteoblasts , 1997, Cell.

[15]  Gerald N. Smith.  The role of collagenolytic matrix metalloproteinases in the loss of articular cartilage in osteoarthritis. , 2006, Frontiers in bioscience : a journal and virtual library.

[16]  E. Cameron,et al.  Gene array analysis reveals a common Runx transcriptional programme controlling cell adhesion and survival , 2008, Oncogene.

[17]  D. Saris,et al.  Cytokine profile of autologous conditioned serum for treatment of osteoarthritis, in vitro effects on cartilage metabolism and intra-articular levels after injection , 2010, Arthritis research & therapy.

[18]  J. E. Thompson,et al.  A Commentary on the Dresden Codex, a Maya Hieroglyphic Book , 1973 .

[19]  D. D’Lima,et al.  Mesenchymal progenitor cell markers in human articular cartilage: normal distribution and changes in osteoarthritis , 2009, Arthritis research & therapy.

[20]  G. Stein,et al.  Identification of novel protein/DNA interactions within the promoter of the bone‐related transcription factor Runx2/Cbfa1 , 2002, Journal of cellular biochemistry.

[21]  S. K. Zaidi,et al.  Runx2 control of organization, assembly and activity of the regulatory machinery for skeletal gene expression , 2004, Oncogene.

[22]  P. D. Kraan,et al.  A role for age-related changes in TGFβ signaling in aberrant chondrocyte differentiation and osteoarthritis , 2010 .

[23]  S. Mundlos,et al.  Cbfa1, a Candidate Gene for Cleidocranial Dysplasia Syndrome, Is Essential for Osteoblast Differentiation and Bone Development , 1997, Cell.

[24]  S. Glasson,et al.  The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. , 2007, Osteoarthritis and cartilage.

[25]  S. Jimenez,et al.  Osteoarthritis cartilage histopathology: grading and staging. , 2006, Osteoarthritis and cartilage.

[26]  A. Uitterlinden,et al.  A new marker for osteoarthritis: cross-sectional and longitudinal approach. , 2004, Arthritis and rheumatism.

[27]  Andrés J. García,et al.  Interactions between integrin ligand density and cytoskeletal integrity regulate BMSC chondrogenesis , 2008, Journal of cellular physiology.

[28]  L. Castilla,et al.  Function of CBFβ/Bro proteins , 2000 .

[29]  M. Lotz.  Posttraumatic osteoarthritis: pathogenesis and pharmacological treatment options , 2010 .

[30]  D. Heinegård,et al.  Release of cartilage oligomeric matrix protein (COMP) into joint fluid after knee injury and in osteoarthritis. , 1994, Annals of the rheumatic diseases.

[31]  S. Goldring,et al.  Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis , 2010, Annals of the New York Academy of Sciences.

[32]  E. Schwarz,et al.  Runx3/AML2/Cbfa3 Regulates Early and Late Chondrocyte Differentiation , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[33]  T. Komori.  Signaling networks in RUNX2‐dependent bone development , 2011, Journal of cellular biochemistry.

[34]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[35]  E. Schwarz,et al.  Runx1/AML1/Cbfa2 Mediates Onset of Mesenchymal Cell Differentiation Toward Chondrogenesis , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[36]  C. De Bari,et al.  The regulation of differentiation in mesenchymal stem cells. , 2010, Human gene therapy.

[37]  H. Fahmi,et al.  Perturbation of adhesion molecule-mediated chondrocyte-matrix interactions by 4-hydroxynonenal binding: implication in osteoarthritis pathogenesis , 2010, Arthritis Research & Therapy.

[38]  Y. Maugars,et al.  From osteoarthritis treatments to future regenerative therapies for cartilage. , 2009, Drug discovery today.