Bone Morphogenetic Proteins (BMPs) are essential regulators of cartilage and bone formation, and understanding their functions in skeletal tissues is crucial to the development of effective therapies for skeletal maintenance and repair. The expression of multiple BMPs in skeletal tissues suggests that these ligands may serve overlapping functions and/or different members play distinct roles in cartilage and bone. Recent studies support each of these possibilities, and raise the additional complexity that a single BMP ligand can have diverse effects, depending on the receptor to which it binds. Specificity of BMP action is thought to be achieved in part by differential affinities of BMP ligands for one of three type I BMP receptors. Moreover, a single BMP acting through a single type of receptor may have diverse effects, depending on the level of receptor activation. Thus, while in vitro studies have been used to great advantage to define the range of activities that can be regulated by BMPs, identifying the physiological roles these growth factors play in cartilage and bone can only be achieved through in vivo studies. In vivo studies utilizing strains of mice deficient in BMP receptors form the basis of this proposal. Mice deficient in BmprIB, and mice carrying a hypomorphic allele of BmprII (BmprIIdeltaE2) will be utilized. In particular, BmprII-/- mice develop severe osteoarthritis, permitting an analysis of the role of BMP signaling pathways in articular cartilage in vivo. The proposed studies will utilize mice carrying a """"""""floxed"""""""" allele of BmprIA (BmprIAfx), which allows this gene to be eliminated in cartilage using Cre/loxP technology, to test the hypothesis that BmprIA and BmprIB exhibit overlapping and unique functions in vivo. All of the strains needed to test this hypothesis have been obtained. The Principal Investigator will also generate mice carrying a floxed allele of ActrI to test the hypothesis that this receptor has unique and essential functions in skeletal tissues. Finally, BmprIIdeltaE2/deltaE2 mice, which are homozygous for a putative hypomorphic (reduced function) allele, exhibit defects in axial patterning and delayed osteogenesis throughout the skeleton. The Principal Investigator will generate a floxed null allele of BmprII using Cre/lox technology. The resulting allelic series will be used to test the hypothesis that different levels of receptor activation cause different cellular responses in cartilage. These experiments are likely to uncover previously unsuspected roles for BMP signaling pathways in cartilage, and to lead to more specific and effective therapies for diseases such as osteoarthritis.
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