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. Recent studies support the theory that osteocytes play a major mechanosensory role. How exactly the osteocyte can sense the mechanical forces applied to the bone and then transform this mechanical stimulus into a biological function remains incompletely understood. Several hormones, particularly prostaglandin E2 (PGE2) and parathyroid hormone (PTH) had been implicated in this process. This proposal will investigate the hypothesis that Gsa- signaling in osteocytes is critical for proper mechano-transduction and bone homeostasis. Moreover, our initial data revealed that lack of Gsa-signaling in osteocytes induce hematopoietic abnormalities.
The first aim of this proposal will test the hypothesis that Gsa-signaling in osteocytes is important for proper bone acquisition and skeletal homeostasis.
The second aim will investigate the hypothesis that Gsa-mediated signaling in osteocyte is an important regulator of mechano-transduction. Lastly, in aim III we will investigate the role of Gsa in hematopoiesis. To address these questions, mice in which Gsa expression is specifically ablated in osteocytes have been generated. To restrict ablation of Gsa to osteocytes, we used the 10Kb upstream promoter of Dentin Matrix Protein-1 (DMP-1), known to be expressed specifically in osteocytes, to drive the Cre-recombinase in mice in which Exon1 of Gnas is flanked by Lox-P sites. This animal model will enable enhanced understanding of Gsa action on bone and on the hematopoietic system and could direct the development of novel therapeutic agents. The studies proposed here will expand the current knowledge on Gsa-signaling in osteocytes and will investigate the extent to which Gsa-dependent pathways in these cells is involved in normal skeletal development, hematopoiesis and mineral-ion homeostasis. In so doing, they promise to significantly expand understanding of osteocyte and bone biology. The hypothesis that we wish to test is that signaling via Gsa in osteocytes directly affects bone homeostasis and mechanosensation and directly, or indirectly controls myeloid cells development and hematopoiesis. If our hypothesis holds true it will be the first time that osteocytes are shown to regulate hematopoiesis.

Public Health Relevance

The studies proposed here will significantly advance our knowledge of the role of Gsa signaling in osteocytes biology and further enhance our understanding of these cells. Results derived from these studies could have significant implications for therapy of bone disorders related to disuse or immobilization. Thus, its relevance is high for skeletal biology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
7R01AR060221-05
Application #
8895067
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Chen, Faye H
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
5
Fiscal Year
2015
Total Cost
$368,475
Indirect Cost
$143,475
Name
Boston University
Department
Biochemistry
Type
Schools of Dentistry
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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
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
Uda, Yuhei; Azab, Ehab; Sun, Ningyuan et al. (2017) Osteocyte Mechanobiology. Curr Osteoporos Rep 15:318-325
Spatz, Jordan M; Wein, Marc N; Gooi, Jonathan H et al. (2015) The Wnt Inhibitor Sclerostin Is Up-regulated by Mechanical Unloading in Osteocytes in Vitro. J Biol Chem 290:16744-58
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
Sinha, Partha; Aarnisalo, Piia; Chubb, Rhiannon et al. (2014) Loss of Gs? early in the osteoblast lineage favors adipogenic differentiation of mesenchymal progenitors and committed osteoblast precursors. J Bone Miner Res 29:2414-26
Divieti Pajevic, Paola (2013) Recent progress in osteocyte research. Endocrinol Metab (Seoul) 28:255-61
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

Showing the most recent 10 out of 12 publications