Osteocytes comprise over 90% of all bone cells, yet little is known of their function(s) or of the involvement of systemic hormones in regulating their activity. These cells reside in the lacunae deep within the mineralized matrix of bone and communicate with one another and with osteoblasts and osteoclasts via gap junctions located at the ends of long cytoplasmic processes that course through tunnels (cannalicula) in the bone. Recent studies support the theory that osteocytes play a major "mechanosensory" role, whereby they are stimulated by shear and stretch forces to produce local cytokines or humoral factors (such as NO and PGE2) and to increase expression of few genes (such as c-fos and IGF-1). Parathyroid hormone (PTH), an 84-amino-acid polypeptide secreted by the parathyroid glands, is a major physiologic regulator of calcium, phosphorous and skeletal homeostasis and, clinically, is the only available anabolic agent to treat osteoporosis. The hormone exerts its effects on target cells via activation of a G-protein coupled receptor, the type-1 PTH/PTHrP receptor (PPR),that is highly expressed in bone and kidney. Cells of the osteoblastic lineage are key targets of PTH action in bone, and recent evidence suggests that osteocytes might be important in the anabolic effects of PTH. The main goal of this project is to understand the role of PPRs in osteocytes and to determine the role(s) of these cells in mediating the effects of the hormone on bone. To address these questions, mice in which PPR expression is specifically ablated in osteocytes will be generated. The 10Kb-DMP1 promoter, active specifically in osteocytes, will drive a Tamoxifen-inducible Cre expression in cells in which the PPR gene is flanked by lox-P sites. In addition a non-inducible 10KbDMP1-Cre and the 8KbDMP1-Cre models will be used and will be provided by our collaborators. This animal models will enable enhanced understanding of PTH action on bone and could direct the development of novel therapeutic agents. These results could have significant implications for therapy of bone disorders such as hyperparathyroidism, osteoporosis and renal osteodystrophy.

Public Health Relevance

If successful this proposal will significantly advance our knowledge of the role of PTH and the PTH receptors in osteocytes and further enhance our understanding of these cells. Results derived from the studies proposed could have significant implications for therapy of bone disorders such as hyperparathyroidism, osteoporosis and renal osteodystrophy. Thus, its relevance is high for skeletal biology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK079161-04
Application #
8248297
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Malozowski, Saul N
Project Start
2009-06-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$377,314
Indirect Cost
$164,142
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Bellido, Teresita; Saini, Vaibhav; Pajevic, Paola Divieti (2013) Effects of PTH on osteocyte function. Bone 54:250-7
Qing, Hai; Ardeshirpour, Laleh; Pajevic, Paola Divieti et al. (2012) Demonstration of osteocytic perilacunar/canalicular remodeling in mice during lactation. J Bone Miner Res 27:1018-29
Powell Jr, William F; Barry, Kevin J; Tulum, Irena et al. (2011) Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses. J Endocrinol 209:21-32