Abstract

Parathyroid hormone-related protein (PTHrP) is an important regulator of the proliferation and differentiation of both chondrocytes and osteoblasts. This project will explore the molecular mechanisms of PTHrP action during bone development. It will also characterize the genes associated with differentiation of chondrocytes and will characterize the differentiation of cells of the osteoblast lineage in vivo. PTHrP suppresses the expression of Runx2 in chondrocytes.
Aim I A will analyze the role of this suppression in mediating the action of PTHrP to delay the differentiation of chondrocytes. Indian hedgehog (Ihh) stimulates the synthesis of PTHrP in chondrocytes. To determine whether the action of Ihh to stimulate PTHrP expression is a direct action on PTHrP-producing chondrocytes, the expression of PTHrP in chondrocytes missing smoothened will be analyzed in chimeric growth plates in Aim IB. To identify genes mediating the action of PTHrP, microarray analysis of E14.5 mouse metatarsals after brief PTH treatment will be performed, and the roles of select genes will be analyzed in Aim 1C. To characterize the genetic changes associated with differentiation of chondrocytes, microarray analysis of RNA amplified from discrete groups of chondrocytes will be conducted in Aim ID, and the roles of select genes will be analyzed. The early stages of differentiation of osteoblast lineage cells and the proliferative capacity of cells at these stages are poorly understood in vivo.
In Aim II, site-specific recombination will be used, with promoters active in early stages of osteoblast development, to study the properties of such cells. Conditionally active recombinases will be used to mark discrete cell populations and determine the self-renewing capacity of these cells both in fetal life and adulthood. Microarrays will be used to characterize genes involved in early steps of the osteoblast lineage. The role of the PTH/PTHrP receptor during fetal osteoblast development will be assessed using a floxxed allele of the PTH/PTHrP receptor.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK056246-10
Application #
7848826
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
10
Fiscal Year
2009
Total Cost
$560,289
Indirect Cost

  Institution

Name
Harvard University
Department
Type
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Chen, J W; Galloway, J L (2017) Using the zebrafish to understand tendon development and repair. Methods Cell Biol 138:299-320
He, Xinjun; Bougioukli, Sofia; Ortega, Brandon et al. (2017) Sox9 positive periosteal cells in fracture repair of the adult mammalian long bone. Bone 103:12-19
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
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
He, Xinjun; Ohba, Shinsuke; Hojo, Hironori et al. (2016) AP-1 family members act with Sox9 to promote chondrocyte hypertrophy. Development 143:3012-23
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 25:2785-2794
Ohba, Shinsuke; He, Xinjun; Hojo, Hironori et al. (2015) Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte. Cell Rep 12:229-43
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
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

Showing the most recent 10 out of 79 publications