The long term goal of this research is to define the molecular mechanisms that control growth and patterning of cartilage, bone, and joint. This is a general proble, in the developent of higher animals, and is of particular relevance to the understanding and treatment of human skeletal diseases, including osteoporosis and osteoarthritis. The studies are specifically directed to understanding the role of bone morphogenetic proteins (BMPs) in normal development. BMPs were originally isolated based on their remarkable ability to induce new caritlage and bone formation when implanted under the skin of animals. The vertebrae genome contains ten or more BMP genes, each expressed in different patterns during normal development. Closely related genes are found in many other organisms, where they control a wide variety of functions, including axis formation, tissue differentiation, and epithelial- mesenchymal interactions. While BMPs are now recognized as one of key classes of signalling molecules in animal development, the large number of different BMPs, and their multiple functions, has hampered studies of their specific role in skeletal development. We have recently shown that two classical mouse genes (short ear and brachypodism) encode two different members of the BMP family. Defects in these genes produce surprisingly specific alterations in particular bone and cartilage elements, and in particular joints. Based on the mutant phenotypes and wxpression patterns of these genes, we have proposed that bMps are the endogenous signals used by embryos to induce the formation of both bones and joints, and that different members of the BMP family control the formation of different sets of skeletal structures. To test this model, we will use two different genetic strategies to examine the functions of other Bmps in mouse development. A dominant negative nutaton will be used to inactivate multiple BMPs in specific skeletal tissues. Knowckout mutations in two new Bmps will be used to test whether different BMPs control formation of different types of joints. Finally, we will use transgenic mice and novel regulatory mutations to define the cis and trans acting factors that control where and when particular bone and joint inducing signals are expressed during normal development. These studies will provide new insights into the basic biological mechanisms that create bones and joints, new tools for maipulating gene expression at specific sites in the skeleton, and may suggest novel strategies for modulating BMP expression in human skeletal diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR042236-08
Application #
6171303
Study Section
Special Emphasis Panel (ZRG4-ORTH (04))
Program Officer
Sharrock, William J
Project Start
1993-08-01
Project End
2002-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
8
Fiscal Year
2000
Total Cost
$451,555
Indirect Cost
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Guenther, Catherine A; Wang, Zhen; Li, Emma et al. (2015) A distinct regulatory region of the Bmp5 locus activates gene expression following adult bone fracture or soft tissue injury. Bone 77:31-41
Foster, B L; Nagatomo, K J; Bamashmous, S O et al. (2011) The progressive ankylosis protein regulates cementum apposition and extracellular matrix composition. Cells Tissues Organs 194:382-405
Dy, Peter; Smits, Patrick; Silvester, Amber et al. (2010) Synovial joint morphogenesis requires the chondrogenic action of Sox5 and Sox6 in growth plate and articular cartilage. Dev Biol 341:346-59
Koyama, Eiki; Shibukawa, Yoshihiro; Nagayama, Motohiko et al. (2008) A distinct cohort of progenitor cells participates in synovial joint and articular cartilage formation during mouse limb skeletogenesis. Dev Biol 316:62-73
Guenther, Catherine; Pantalena-Filho, Luiz; Kingsley, David M (2008) Shaping skeletal growth by modular regulatory elements in the Bmp5 gene. PLoS Genet 4:e1000308
Ho, Andrew M; Marker, Paul C; Peng, Hairong et al. (2008) Dominant negative Bmp5 mutation reveals key role of BMPs in skeletal response to mechanical stimulation. BMC Dev Biol 8:35
Koyama, Eiki; Ochiai, Takanaga; Rountree, Ryan B et al. (2007) Synovial joint formation during mouse limb skeletogenesis: roles of Indian hedgehog signaling. Ann N Y Acad Sci 1116:100-12
Feldman, George J; Billings, Paul C; Patel, Rajesh V et al. (2007) Over-expression of BMP4 and BMP5 in a child with axial skeletal malformations and heterotopic ossification: a new syndrome. Am J Med Genet A 143:699-706
Gurley, Kyle A; Reimer, Richard J; Kingsley, David M (2006) Biochemical and genetic analysis of ANK in arthritis and bone disease. Am J Hum Genet 79:1017-29

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