This Program Project consists of three closely related and integrated proposals focusing on signals that regulate skeletal morphogenesis during embryonic development. The projects are highly coordinated, founded in the last 10 years of a highly successful Program Project and with a long history of collaborative efforts before that. A unique feature of this team is the exchange of expertise between laboratories whose primary focus has been either developmental skeletal biology (Tabin, McMahon) or endocrine control of skeletogenesis (Kronenberg). The high-resolution histology core extends the technical capabilities of each individual lab. All three projects are focused on dissecting the roles of key regulatory pathways in skeletal development. Project 1 will examine the mechanisms used by parathyroid hormone-related protein (PTHrP) and associated G-proteins in regulating these processes and will determine the roles of novel regulators of Chondrocyte differentiation discovered in the last grant cycle, as well as characterizing the early cells of the osteoblast lineage and their relationship with the perichondrium. PTHrP works in a feedback loop with a second secreted protein;Indian hedgehog (Ihh). Project 3 will explore the role of extracellular matrix in modulating Ihh signaling and will also study the role of the perichondrium in signaling to and controlling growth and differentiation of the cartilage elements. Project 2 is devoted to defining the regulatory networks involved in chondrogenesis and osteogenesis within the skeletal elements themselves. These projects are knit together by common themes, complimentary approaches, shared reagents, and direct collaborations. Together these highly related projects will achieve a new level of understanding of the regulation of bone morphogenesis which could not be attained by independent efforts.

Public Health Relevance

This Program Project focuses on the intercellular signals that control the growth of the developing skeletal tissues. Because the same regulatory networks are utilized post-natally as the skeleton grows, remodels and repairs itself, these studies will also increase understanding of medically relevant aspects of bone physiology, including regulation of the post-natal growth plate and control of bone healing and remodeling following fractures

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK056246-14
Application #
8663234
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Malozowski, Saul N
Project Start
1999-08-20
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Hojo, Hironori; McMahon, Andrew P; Ohba, Shinsuke (2016) An Emerging Regulatory Landscape for Skeletal Development. Trends Genet 32:774-787
Finch, Caleb E; McMahon, Andrew P (2016) Stem cells for all ages, yet hostage to aging. Stem Cell Investig 3:11
He, Xinjun; Ohba, Shinsuke; Hojo, Hironori et al. (2016) AP-1 family members act with Sox9 to promote chondrocyte hypertrophy. Development 143:3012-23
Hojo, Hironori; Ohba, Shinsuke; He, Xinjun et al. (2016) Sp7/Osterix Is Restricted to Bone-Forming Vertebrates where It Acts as a Dlx Co-factor in Osteoblast Specification. Dev Cell 37:238-53
Ohba, Shinsuke; He, Xinjun; Hojo, Hironori et al. (2015) Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte. Cell Rep 12:229-43
Ono, Noriaki; Kronenberg, Henry M (2015) Mesenchymal progenitor cells for the osteogenic lineage. Curr Mol Biol Rep 1:95-100
Hirai, Takao; Kobayashi, Tatsuya; Nishimori, Shigeki et al. (2015) Bone Is a Major Target of PTH/PTHrP Receptor Signaling in Regulation of Fetal Blood Calcium Homeostasis. Endocrinology 156:2774-80
Kozhemyakina, Elena; Zhang, Minjie; Ionescu, Andreia et al. (2015) Identification of a Prg4-expressing articular cartilage progenitor cell population in mice. Arthritis Rheumatol 67:1261-73
Moore, Talia Y; Organ, Chris L; Edwards, Scott V et al. (2015) Multiple phylogenetically distinct events shaped the evolution of limb skeletal morphologies associated with bipedalism in the jerboas. Curr Biol 25:2785-94
Manolagas, Stavros C; Kronenberg, Henry M (2014) Reproducibility of results in preclinical studies: a perspective from the bone field. J Bone Miner Res 29:2131-40

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