Abstract

Parathyroid hormone (PTH) is the best characterized of the small group of agents that increase bone formation and may become part of a therapy for osteoporosis capable of restoring normal bone mass in this patient group. The actions of parathyroid hormone are mediated by a common receptor for both PTH and PTH-related protein (PTHrP) and involve increases in both bone formation and resorption. The goal of this proposal is to evaluate, in vivo, the roles of PTH and PTH~P in regulating osteoblast and osteoclast development and function by specifically deleting the PTH/PTHrP receptor gene from cells of the osteoblast lineage.
The first aim will be to establish lines of mice selectively missing the PTH/PTHrP receptor gene only in osteoblasts of varying degrees of maturity. The cre-lox system will be used to generate mice missing the PTH/PTHrP receptor gene in osteoblasts that express the alpha1(I) collagen gene promoter and in those that express the osteocalcin gene promoter.
The second aim will be to assess the role of the PTH/PTHrP receptor in osteoblast development and function. Histomorphometry, BRdU labeling, and in situ hybridization will be used to assess abnormalities of osteoblast development and function. Comparisons of the two types of cre-lox mice will clarify the relative roles of osteoblasts of varying degrees of maturity. Mice missing the PTH gene will be used to assess the individual roles of PTH and PTHrP in activating the PTH/PTHrP receptor to control osteoblast development and function.
The third aim will be to assess the role of the PTH/PTHrP receptor in osteoclast development and function. Histomorphometry, urinary markers of bone resorption, and in situ hybridization will be used to assess abnormalities of osteoclast development and function. Comparisons of the two types of cre-lox mice and the use of mice missing the PTH gene will clarify the roles of osteoblasts of differing levels of maturity and the relative roles of PTH and PTHrP. These studies will lead to a better understanding of the potentially conflicting actions of PTH on bone and may lead to more effective use of PTH-like drugs in the treatment of osteoporosis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center (P50)
Project #
5P50AR044855-03
Application #
6201544
Study Section
Project Start
1999-09-01
Project End
2000-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
3
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

Yu, Elaine W; Neer, Robert M; Lee, Hang et al. (2011) Time-dependent changes in skeletal response to teriparatide: escalating vs. constant dose teriparatide (PTH 1-34) in osteoporotic women. Bone 48:713-9
Finkelstein, Joel S; Wyland, Jason J; Lee, Hang et al. (2010) Effects of teriparatide, alendronate, or both in women with postmenopausal osteoporosis. J Clin Endocrinol Metab 95:1838-45
Finkelstein, Joel S; Wyland, Jason J; Leder, Benjamin Z et al. (2009) Effects of teriparatide retreatment in osteoporotic men and women. J Clin Endocrinol Metab 94:2495-501
Leder, Benjamin Z; Neer, Robert M; Wyland, Jason J et al. (2009) Effects of teriparatide treatment and discontinuation in postmenopausal women and eugonadal men with osteoporosis. J Clin Endocrinol Metab 94:2915-21
Finkelstein, Joel S; Leder, Benjamin Z; Burnett, Sherri-Ann M et al. (2006) Effects of teriparatide, alendronate, or both on bone turnover in osteoporotic men. J Clin Endocrinol Metab 91:2882-7
Kobayashi, Tatsuya; Kronenberg, Henry M; Foley, John (2005) Reduced expression of the PTH/PTHrP receptor during development of the mammary gland influences the function of the nipple during lactation. Dev Dyn 233:794-803
Miao, Dengshun; He, Bin; Jiang, Yebin et al. (2005) Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34. J Clin Invest 115:2402-11
Inada, Masaki; Wang, Yingmin; Byrne, Michael H et al. (2004) Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. Proc Natl Acad Sci U S A 101:17192-7
Kuznetsov, Sergei A; Riminucci, Mara; Ziran, Navid et al. (2004) The interplay of osteogenesis and hematopoiesis: expression of a constitutively active PTH/PTHrP receptor in osteogenic cells perturbs the establishment of hematopoiesis in bone and of skeletal stem cells in the bone marrow. J Cell Biol 167:1113-22
Chiusaroli, R; Maier, A; Knight, M C et al. (2003) Collagenase cleavage of type I collagen is essential for both basal and parathyroid hormone (PTH)/PTH-related peptide receptor-induced osteoclast activation and has differential effects on discrete bone compartments. Endocrinology 144:4106-16

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