Abstract

The hormone, parathyroid hormone (PTH), and the paracrine factor, parathyroid hormone-related protein (PTHrP) help regulate both bone growth and calcium homeostasis through interactions with a common PTH/PTHrP receptor. This signaling system interacts with other signaling systems-including those triggered by Indian hedgehog (Ihh), bone morphogenic proteins (BMPs), and cytokines that activate gpl30-to assure normal growth and calcium regulation. Genetically altered mice, including chimeric mice of mixed genetic lineage, will be used to understand the interactions of these signaling systems in vivo.
Aim I will study regulation of the growth plate by PTHrP and Ihh through the use of chimeric mice. The role of a feedback loop between PTHrP and Ihh signaling in controlling the rate of chondrocyte differentiation will be assessed, and the role of Ihh in regulating differentiation of adjacent bone cells will be studied. The interactions of BMPs and PTHrP will be analyzed through matings that involve mice transgenic for expression of a constitutively active BMR receptor 1A. The effect of deleting the PTHrP gene from these mice will be analyzed. The lineage relationships of chondrocytes and osteoblasts will be analyzed by studying the fates of genetically marked chondrocytes in chimeric mice.
Aim II will analyze the prenatal function of PTH through the study of PTH (-/-) mice. The distinct roles of PTH, PTHrP and the PTH/PTHrP receptor in bone growth and calcium homeostasis will be analyzed by appropriate matings, followed by analyses of bone structure and parameters of calcium homeostasis.
Aim III will study the interactions between PTH/PTHrP receptor signaling and gp130 signaling in stimulating osteoblast lineage cells, which then activate osteoclastogenesis and osteoclast action. Calcium homeostasis will be studied prenatally in gp130 (-/-) mice. The interactions between PTH and gp130 signaling will be studied in chimeric mice and in cell mixing experiments. Together, these studies will define the relationships of important signaling pathways in regulating normal bone development and calcium homeostasis in vivo.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK047038-06
Application #
2850003
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Margolis, Ronald N
Project Start
1994-06-01
Project End
1999-07-31
Budget Start
1999-06-01
Budget End
1999-07-31
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Rubin, Lewis P; Kovacs, Christopher S; De Paepe, Monique E et al. (2004) Arrested pulmonary alveolar cytodifferentiation and defective surfactant synthesis in mice missing the gene for parathyroid hormone-related protein. Dev Dyn 230:278-89
Rossi, Ferdinand; MacLean, Helen E; Yuan, Wei et al. (2002) p107 and p130 Coordinately regulate proliferation, Cbfa1 expression, and hypertrophic differentiation during endochondral bone development. Dev Biol 247:271-85
Kovacs, C S; Manley, N R; Moseley, J M et al. (2001) Fetal parathyroids are not required to maintain placental calcium transport. J Clin Invest 107:1007-15
Huang, W; Chung, U I; Kronenberg, H M et al. (2001) The chondrogenic transcription factor Sox9 is a target of signaling by the parathyroid hormone-related peptide in the growth plate of endochondral bones. Proc Natl Acad Sci U S A 98:160-5
Lanske, B; Amling, M; Neff, L et al. (1999) Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development. J Clin Invest 104:399-407
Divieti, P; Lanske, B; Kronenberg, H M et al. (1998) Conditionally immortalized murine osteoblasts lacking the type 1 PTH/PTHrP receptor. J Bone Miner Res 13:1835-45
Lanske, B; Kronenberg, H M (1998) Parathyroid hormone-related peptide (PTHrP) and parathyroid hormone (PTH)/PTHrP receptor. Crit Rev Eukaryot Gene Expr 8:297-320
Lanske, B; Divieti, P; Kovacs, C S et al. (1998) The parathyroid hormone (PTH)/PTH-related peptide receptor mediates actions of both ligands in murine bone. Endocrinology 139:5194-204
Kronenberg, H M; Lanske, B; Kovacs, C S et al. (1998) Functional analysis of the PTH/PTHrP network of ligands and receptors. Recent Prog Horm Res 53:283-301;discussion 301-3
Chung, U I; Lanske, B; Lee, K et al. (1998) The parathyroid hormone/parathyroid hormone-related peptide receptor coordinates endochondral bone development by directly controlling chondrocyte differentiation. Proc Natl Acad Sci U S A 95:13030-5

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