(Taken from the application): Despite impressive advances in understanding of osteoporosis, the cure of osteoporosis remains an elusive goal. When patients present with fractures, the loss of bone has already been quite substantial. An important goal must be to increase the strength of such bone to normal. Since currently available treatments all focus on inhibiting resorption of bone, these treatments cannot restore bone mass to normal. A safe and effective agent that increases bone formation in osteoporotic patients, therefore, is required for the cure of osteoporosis. Parathyroid hormone (PTH), administered by once daily injection to humans or to a variety of animal species, increases bone mass and bone strength by increasing bone formation, and prevents fractures. Consideration of the complicated actions of parathyroid hormone on bone leads to the realization that very little is understood about the basic mechanisms of PTH action. Greater understanding of these basic mechanisms will facilitate the design of strategies for clinical use of PTH. The goal of this proposed SCOR (a continuation of funding begun in October 1997) is to learn how to use parathyroid hormone to treat patients with osteoporosis in the most effective manner. Achievement of this goal will require a combined approach that both evaluates the effects parathyroid hormone in humans and studies the basic mechanisms of parathyroid hormone action in animal models. The SCOR has as its centerpiece a patient-based project that explores the effects of administering PTH to osteoporotic men and women. The goals are to understand the mechanisms of the anabolic action of PTH and, thereby, to determine how best to use PTH in the treatment of osteoporosis. Three projects then explore the cellular and molecular basis of the actions of parathyroid hormone on bone. Each of these three projects studies the actions of PTH on bone in vivo and uses precise genetic manipulations in mice to probe mechanisms without abandoning the complexity of the intact animal. A Bone Analysis Core Facility will provide skills efficiencies in the analysis of samples of blood, urine, and bone that will aid each of the four scientific projects. An Administrative Core will assure that communication between the various projects is optimal and will monitor the progress of each project.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center (P50)
Project #
5P50AR044855-06
Application #
6534440
Study Section
Special Emphasis Panel (ZAR1-TLB-C (M1))
Program Officer
Freeman, Julia B
Project Start
1997-09-22
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
6
Fiscal Year
2002
Total Cost
$1,155,844
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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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