BMPs in Skeletal Growth and Osteogenic Differentiation

University Of California Los Angeles, Los Angeles CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): 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. [unreadable] [unreadable]