Chondrogenesis is a process of ordered and synchronous differentiation of mesenchymal cells into chondrocytes. Endochondral ossification is a process of chondrocyte differentiation that determines skeletal growth. Our goal is to better understand the signaling and transcriptional pathways that control (i) commitment of mesenchymal cells to the chondrocyte cell lineage and (ii) the differentiation of chondrocytes during endochondral ossification. In the pursuit of this goal, we have identified a novel pathway that induces chondrogenesis and chondrocyte gene expression. In this pathway, elevation of intracellular calcium causes sequential activation of (i) calcineurin and (ii) the transcription factor, nuclear factor of activated T-cell 4 (NFAT4). NFAT4 then enters the nucleus and directly induces BMP-2 gene expression. In turn, BMP-2 acts as an autocrine/paracrine inducer of differentiation. Because calcium-dependent signaling is induced by many growth factors/hormones and basic cell biological processes, we hypothesize that calcium-dependent activation of NFATs and induction of BMP expression is a central pathway regulating chondrogenesis and chondrocyte differentiation. To test this hypothesis and further our understanding of chondrocyte differentiation we will pursue the following Specific Aims: (1) determine the effects of NFAT1, 2, and 3 on chondrogenesis and BMP expression, (2) elucidate the effect of calcineurin and NFAT4 on chondrogenesis and chondrocyte differentiation in vivo, (3) investigate the kinase control of NFATs during chondrogenesis/chondrocyte gene expression, and (4) analyze the transcriptional control of the BMP-2 gene by NFATs and cooperating regulators of transcription. These studies will utilize many reagents created during our preliminary studies and will fundamentally advance our understanding of chondrogenesis and chondrocyte differentiation. We anticipate that these studies will suggest novel ways to promote cartilage regeneration or suppress cartilage degeneration. ? ?

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Tyree, Bernadette
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Health Science Center San Antonio
Other Domestic Higher Education
San Antonio
United States
Zip Code
Geng, Hui; Lan, Rongpei; Wang, Guichun et al. (2009) Inhibition of autoregulated TGFbeta signaling simultaneously enhances proliferation and differentiation of kidney epithelium and promotes repair following renal ischemia. Am J Pathol 174:1291-308
Reinhold, Martina I; Naski, Michael C (2007) Direct interactions of Runx2 and canonical Wnt signaling induce FGF18. J Biol Chem 282:3653-63
Reinhold, Martina I; Kapadia, Ravi M; Liao, Zhixiang et al. (2006) The Wnt-inducible transcription factor Twist1 inhibits chondrogenesis. J Biol Chem 281:1381-8
Kapadia, Ravi M; Guntur, Anyonya R; Reinhold, Martina I et al. (2005) Glycogen synthase kinase 3 controls endochondral bone development: contribution of fibroblast growth factor 18. Dev Biol 285:496-507
Reinhold, Martina I; Abe, Makoto; Kapadia, Ravi M et al. (2004) FGF18 represses noggin expression and is induced by calcineurin. J Biol Chem 279:38209-19
Abe, Makoto; Naski, Michael C (2004) Regulation of sprouty expression by PLCgamma and calcium-dependent signals. Biochem Biophys Res Commun 323:1040-7