This proposal investigates the roles of bone morphogenetic proteins (BMPs) in chondrogenesis. Through analysis of mice lacking BMPR1A and/or BMPR1B, we demonstrated that signaling through these receptors is essential for chondrocyte proliferation, differentiation, and maintenance. These studies showed that BMPR1A and BMPR1B have overlapping functions at the condensation stage, but did not reveal the extent to which they collaborate at later stages. Moreover, while ActRI is insufficient on its own to support chondrogenesis beyond the condensation stage, the extent to which BMPR1A and/or BMPR1B alone can promote chondrogenesis is unknown. Resolution of this issue is important for future strategies targeted toward activation of specific BMP receptors in order to elicit defined responses in tissue engineering applications or in repair in vivo. We address these issues in Aim 1 through characterization ActRI/Bmprla and ActRI/Bmprlb double mutants, and through the generation of mice in which loss of BMP receptor function can be induced at late gestation stages. It is likely that BMPs transduce the majority of their effects through Smads, but it is unknown whether or not all 3 BMP-specific Smads are required for chondrogenesis, or whether Smads have distinct vs. overlapping functions. We address this issue in aim two. Studies of Bmpr1a/1b compound mutants uncovered evidence that loss of BMP signaling is accompanied by increased output from FGF pathways. This finding suggests that BMP and FGF pathways act antagonistically during chondrogenesis, and raises the possibility that the relative balance between BMP and FGF signaling is a major determinant of chondrocyte progression through the growth plate. We test this and identify downstream components of FGF signaling pathways responsible for these effects in aim three through construction of mice in which relative output from BMP and FGF pathways is altered, and through the use of limb cultures. Analysis of BMP receptor mutants demonstrated that BMP pathways are essential for expression of Ihh, the key regulator of chondrocyte proliferation and differentiation in the growth plate. It has been shown in vitro that ERK1/2 antagonizes BMP signaling by directly phosphorylating, and thereby inactivating, BMP-specific Smads.
In aim four, we test whether this mechanism is relevant to Ihh expression in the growth plate. Understanding how BMPs control distinct aspects of chondrogenesis and how FGFs antagonize these effects is vital to understanding how BMPs can be utilized most optimally in tissue engineering applications, for cartilage repair and maintenance, and potentially for treatment of chondrodysplasias caused by activating FGF mutations. ? ?
| Wang, Weiguang; Song, Buer; Anbarchian, Teni et al. (2016) Smad2 and Smad3 Regulate Chondrocyte Proliferation and Differentiation in the Growth Plate. PLoS Genet 12:e1006352 |
| Rigueur, Diana; Brugger, Sean; Anbarchian, Teni et al. (2015) The type I BMP receptor ACVR1/ALK2 is required for chondrogenesis during development. J Bone Miner Res 30:733-41 |
| Nishida, Takashi; Kubota, Satoshi; Aoyama, Eriko et al. (2015) CCN family protein 2 (CCN2) promotes the early differentiation, but inhibits the terminal differentiation of skeletal myoblasts. J Biochem 157:91-100 |
| Weinstein, Michael M; Tompson, Stuart W; Chen, Yuqing et al. (2014) Mice expressing mutant Trpv4 recapitulate the human TRPV4 disorders. J Bone Miner Res 29:1815-1822 |
| Rigueur, Diana; Lyons, Karen M (2014) Whole-mount skeletal staining. Methods Mol Biol 1130:113-121 |
| Güemes, Miriam; Garcia, Alejandro J; Rigueur, Diana et al. (2014) GATA4 is essential for bone mineralization via ER? and TGF?/BMP pathways. J Bone Miner Res 29:2676-87 |
| Ascenzi, Maria-Grazia; Du, Xia; Harding, James I et al. (2014) Automated Cell Detection and Morphometry on Growth Plate Images of Mouse Bone. Appl Math (Irvine) 5:2866-2880 |
| Wang, Weiguang; Rigueur, Diana; Lyons, Karen M (2014) TGF? signaling in cartilage development and maintenance. Birth Defects Res C Embryo Today 102:37-51 |
| Estrada, Kristine D; Wang, Weiguang; Retting, Kelsey N et al. (2013) Smad7 regulates terminal maturation of chondrocytes in the growth plate. Dev Biol 382:375-84 |
| Merrill, Amy E; Sarukhanov, Anna; Krejci, Pavel et al. (2012) Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling. Am J Hum Genet 90:550-7 |
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