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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Malozowski, Saul N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Fulzele, Keertik; Dedic, Christopher; Lai, Forest et al. (2018) Loss of Gs? in osteocytes leads to osteopenia due to sclerostin induced suppression of osteoblast activity. Bone 117:138-148
Dedic, Christopher; Hung, Tin Shing; Shipley, Alan M et al. (2018) Calcium fluxes at the bone/plasma interface: Acute effects of parathyroid hormone (PTH) and targeted deletion of PTH/PTH-related peptide (PTHrP) receptor in the osteocytes. Bone 116:135-143
Shi, Chao; Uda, Yuhei; Dedic, Christopher et al. (2018) Carbonic anhydrase III protects osteocytes from oxidative stress. FASEB J 32:440-452
Fulzele, Keertik; Lai, Forest; Dedic, Christopher et al. (2017) Osteocyte-Secreted Wnt Signaling Inhibitor Sclerostin Contributes to Beige Adipogenesis in Peripheral Fat Depots. J Bone Miner Res 32:373-384
Panaroni, Cristina; Fulzele, Keertik; Saini, Vaibhav et al. (2015) PTH Signaling in Osteoprogenitors Is Essential for B-Lymphocyte Differentiation and Mobilization. J Bone Miner Res 30:2273-86
Saini, Vaibhav; Marengi, Dean A; Barry, Kevin J et al. (2013) Parathyroid hormone (PTH)/PTH-related peptide type 1 receptor (PPR) signaling in osteocytes regulates anabolic and catabolic skeletal responses to PTH. J Biol Chem 288:20122-34
Fulzele, Keertik; Krause, Daniela S; Panaroni, Cristina et al. (2013) Myelopoiesis is regulated by osteocytes through Gs?-dependent signaling. Blood 121:930-9
Bellido, Teresita; Saini, Vaibhav; Pajevic, Paola Divieti (2013) Effects of PTH on osteocyte function. Bone 54:250-7
Kim, Sang Wan; Pajevic, Paola Divieti; Selig, Martin et al. (2012) Intermittent parathyroid hormone administration converts quiescent lining cells to active osteoblasts. J Bone Miner Res 27:2075-84
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

Showing the most recent 10 out of 11 publications