TGF-beta has been implicated as a critical regulator of the rate of chondrocyte maturation in the post-natal animal. Our preliminary data demonstrates that TGF-beta induces chondrogenesis and inhibits chondrocyte maturation, and activates both Smad and ATF-2 signaling events Finally, our data suggest that Smad3 and ATF-2 act cooperatively to mediate TGF-beta effects in chondrocytes. The current proposal uses a genetic approach, with complementary in vitro and in vivo murine models, to examine the hypothesis that both Smad3 and ATF-2 are critical molecular effectors of TGF-beta effects on chondrogenesis and chondroctye maturation and work cooperatively to mediate TGF-beta effects.
Aim I examines the role of Smad3 and ATF-2 as effectors of TGF-beta signaling during chodrogenesis and chondrocyte differentiation using murine cells deficient in Smad3 and ATF-2, alone or in combination.
In Aim 2, deletion of ATF-2 is targeted to cartilage through the development of a coI2A-CRE;ATF-2 loxP mouse. The ATF-2 -/- mouse dies at birth of pulmonary disease, but it is our hypothesis that the conditional mutation will have premature chondrocyte maturation post natal and will develop progressively abnormal growth and joint function, as observed in Smad3 -/- mice. Furthermore, we hypothesize that crossing these animals with Smad3 -/- mice will result in a phenotype more severe than that observed in animals with a single gene deletion.
In Aim 3 we examine the role of Smad3 and ATF-2 on skeletal repair, using murine in vivo ectopic endochondral bone formation and fracture healing models. These studies will examine the hypothesis that the TGF-beta signaling molecules Smad3 and ATF-2 are essential for normal endochondral bone repair in the post natal animal. We further hypothesize that combined deletion of Smad3 and ATF-2 will result in a more severe phenotype with more profound abnormalities in endochondral bone repair. Thus, the experiments use a genetic approach to examine the role of TGF-beta signaling on skeletal growth and development, osteoarthritis, and tissue repair and have great potential to define important molecular targets that can directly benefit orthopaedic patients. ? ?
|Zhang, Yongchun; Sheu, Tzong-jen; Hoak, Donna et al. (2016) CCN1 Regulates Chondrocyte Maturation and Cartilage Development. J Bone Miner Res 31:549-59|
|Dao, Debbie Y; Jonason, Jennifer H; Zhang, Yongchun et al. (2012) Cartilage-specific ?-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development. J Bone Miner Res 27:1680-94|
|Gunnell, Lea M; Jonason, Jennifer H; Loiselle, Alayna E et al. (2010) TAK1 regulates cartilage and joint development via the MAPK and BMP signaling pathways. J Bone Miner Res 25:1784-97|
|Wu, Qiuqian; Kim, Kyung-Ok; Sampson, Erik R et al. (2008) Induction of an osteoarthritis-like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice. Arthritis Rheum 58:3132-44|
|Li, Tian-Fang; Darowish, Michael; Zuscik, Michael J et al. (2006) Smad3-deficient chondrocytes have enhanced BMP signaling and accelerated differentiation. J Bone Miner Res 21:4-16|
|Li, Tian-Fang; O'Keefe, Regis J; Chen, Di (2005) TGF-beta signaling in chondrocytes. Front Biosci 10:681-8|
|Li, Tian-Fang; Zuscik, Michael J; Ionescu, Andreia M et al. (2004) PGE2 inhibits chondrocyte differentiation through PKA and PKC signaling. Exp Cell Res 300:159-69|
|Li, Xuefeng; Schwarz, Edward M; Zuscik, Michael J et al. (2003) Retinoic acid stimulates chondrocyte differentiation and enhances bone morphogenetic protein effects through induction of Smad1 and Smad5. Endocrinology 144:2514-23|
|Zhang, Donghui; Ferguson, Cristin M; O'Keefe, Regis J et al. (2002) A role for the BMP antagonist chordin in endochondral ossification. J Bone Miner Res 17:293-300|
|Ionescu, A M; Schwarz, E M; Vinson, C et al. (2001) PTHrP modulates chondrocyte differentiation through AP-1 and CREB signaling. J Biol Chem 276:11639-47|
Showing the most recent 10 out of 14 publications