Paola Divieti Pajevic

Funding
Members

Education

PhD (Molecular and Cell Biology), University of Florence, 1995; MD, University of Milan, 1990

Research Description

Divieti Pajevic Laboratory investigates the effects of hormones (parathyroid hormone; PTH), intracellular signaling (Gsα subunit) and mechanical forces (gravity) on osteocytes both “in vivo”, using genetically modified animal models, and “in vitro” using novel osteocytic cell line. Osteocytes, the most abundant cells in bone, are the cells that 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. Their relative inaccessibility and (until recently) the lack of good in vitro cell models have impeded progress in understanding their functional roles. Although it is well established that bone responds to its mechanical environment, the mechanisms underlying mechano-transduction are poorly understood.

Osteocytes are targets for numerous systemic hormones including PTH, which acts through the PTH/PTHrP receptor (PPR). Clinically, PTH is the only available anabolic agent to treat osteoporosis. Moreover, recent evidence from us and other groups, suggests that osteocytes may partially mediate the anabolic effects of PTH via PTH mediated suppression of the osteocyte-specific protein sclerostin, a potent Wnt signaling inhibitor. To understand the role of PPR signaling in osteocytes and to determine if osteocytes directly mediate the effects of PTH on bone, we have generated mice with osteocyte-specific ablation of PPR (DMP1-PPRKO) using Cre-loxP recombination technique. Use of this model promise to greatly enhance understanding of PTH action in osteocytes and possibly lead to the development of novel therapeutic agents for osteoporosis or other osteopenic diseases. The project is funded by an RO1 from NIDDK

Similarly, to investigate the role of Gsα in osteocytes, we have engineered mice lacking Gsα in these cells by using the Cre-loxP recombination technique. Consistent with the role of osteocytes in regulating bone remodeling, GsαKO mice showed severe osteopenia. Unexpectedly, these mice also displayed hematopoietic abnormalities characterized by increased number of granulocytes and monocytes both in the bone marrow and in the spleen, suggesting an important role of osteocytes in the bone hematopoietic niche. The project is currently funded by an RO1 from NIAMS.

Lastly, in an effort to investigate the role of gravity, or the lack of it, in osteocytes, we have established conditionally immortalized osteocytic cell lines that faithfully recapitulate all the characteristics of an “osteocyte”. These cells are characterized and selected on the basis of their responses to PTH and their secretion of osteocytes specific protein, such as Sclerostin. These cell line will be flown on the International Space Station (ISS) on board the SpaceX-6, launched on April 13^th 2015. Main aim of this space project is to study, at the cellular and molecular level, mechanisms of mechano-transduction. This will be the first experiment to study osteocytes exposed to microgravity. These studies will provide insights into mechano-transduction pathways and are a first step towards a better understanding the role of osteocytes in modulating mechano-transduction. (see NASA link http://www.nasa.gov/mission_pages/station/research/experiments/1276.html)

Selected Publications

1. Kim SW, Pajevic PD, Selig M, Barry KJ, Yang JY, Shin CS, Baek WY, Kim JE, Kronenberg HM. (2012). Intermittent parathyroid hormone administration converts quiescent lining cells to active osteoblasts. J Bone Miner Res. 27(10):2075-84. PMCID: PMC3529414.
2. Spatz JM, Fields EE, Yu EW, Divieti Pajevic P, Bouxsein ML, Sibonga JD, Zwart SR, Smith SM. Serum Sclerostin increases in healthy adult men during bed rest. J Clin Endocrinol Metab. 2012 Sep;97(9):E1736-40. doi: 10.1210/jc.2012-1579. Epub 2012 Jul 5.
3. Fulzele K, Krause D, Panaroni C, Saini V, Barry KJ, Liu X, Feng JQ, Chen M , Weinstein LS, Wu JY, Kronenberg HM, Scadden DT, Divieti Pajevic P “Myelopoiesis is regulated by osteocytes through Gsα-dependent signaling” Blood. 2013 Feb 7;121(6):930-9. doi: 10.1182/blood-2012-06-437160. Epub 2012 Nov 16.PMID: 23160461
4. Saini. V, Marengi. DJ, Barry KJ, Fulzele KS, Heiden E, Liu X., Dedic C., Maeda A., Lotinun S, Roland Baron R. and Divieti Pajevic P. ”Parathyroid Hormone (PTH)/PTH-related Peptide Type 1 Receptor (PPR) Signaling in Osteocytes Regulates Anabolic and Catabolic Skeletal Responses to PTH”  J. Biol. Chem. J Biol Chem. 2013 Jul 12;288(28):20122-34. doi: 10.1074/jbc.M112.441360. Epub 2013 Jun 2. PMID: 23729679
5. Christov M, Waikar SS, Pereira RC, Havasi A, Leaf DE, Goltzman D, Divieti Pajevic P, Wolf M, Jüppner H. Plasma FGF23 levels increase rapidly after acute kidney injury Kidney Int. 2013 Oct;84(4):776-85. doi: 10.1038/ki.2013.150. Epub 2013 May 8.PMID: 23657144
6. Windahl SH, Börjesson AE, Farman HH, Engdahl C, Movérare-Skrtic S, Sjögren K, Lagerquist MK, Kindblom JM, Koskela A, Tuukkanen J, Divieti Pajevic P, Feng JQ, Dahlman-Wright K, Antonson P, Gustafsson JÅ, Ohlsson C. Estrogen receptor-α in osteocytes is important for trabecular bone formation in male mice. Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2294-9. doi: 10.1073/pnas.1220811110. Epub 2013 Jan 23, PMID: 23345419
7. Sinha P, Aarnisalo P, Chubb R, Ono N, Fulzele K, Selig M, Saeed H, Chen M, Weinstein LS, Divieti Pajevic P, Kronenberg HM, Wu JY.Loss of Gs α Early in the Osteoblast Lineage Favors Adipogenic Differentiation of Mesenchymal Progenitors and Committed Osteoblast PrecursorsJ Bone Miner Res. 2014 May 7. doi: 10.1002/
8. Krause DS, Fulzele K, Catic A, Sun CC, Dombkowski D, Hurley MP, Lezeau S, Attar E, Wu JY, Lin HY, Divieti Pajevic P, Hasserjian RP, Schipani E, Van Etten RA, Scadden DT “Differential regulation of myeloid leukemias by the bone marrow microenvironment”, Nat Med. 2013 Nov;19(11):1513-7. doi: 10.1038/nm.3364. Epub 2013 Oct 27, PMID: 24162813
9. Divieti Pajevic P. Resent progress in osteocytes research Endocrinol Metab (Seoul). 2013 Dec;28(4):255-61. doi: 10.3803/EnM.2013.28.4.255. Review. PMID: 24396689
10. Wein MN, Spatz J, Nishimori S, Doench J, Root D, Babij P, Nagano K, Baron R, Brooks D, Bouxsein M, Divieti Pajevic P, Kronenberg HM. HDAC5 controls MEF2C-driven Sclerostin expression in osteocytes J Bone Miner Res. 2015 Mar;30(3):400-11. doi: 10.1002/jbmr.2381 PMID: 25271055
11. Spatz JM, Wein MN, Gooi JH, Qu Y, Garr JL, Liu S, Barry KJ, Uda Y, Lai F, Dedic C, Balcells-Camps M, Kronenberg HM, Babij P, Divieti Pajevic P. The Wnt-inhibitor Sclerostin is up-regulated by Mechanical Unloading in Osteocytes in-vitro J Biol Chem. 2015 May 7. pii: jbc.M114.628313. [Epub ahead of print] PMID: 25953900