We propose that the actions of parathyroid hormone (PTH) are modified at the cellular level by the PTH induction of cyclooxygenase-2 (COX-2) and COX-2-produced prostaglandins (PGs). PTH is a systemic hormone acting predominantly on osteoblast (OB) lineage cells, whereas PGs are autocrine/paracrine lipids acting on both OB and osteoclast (OC) lineage cells. PTH is a potent inducer of COX-2 and PGs in OBs. Although PTH is generally thought to be osteogenic or anabolic only when given intermittently, continuous exposure to PTH markedly stimulates OB differentiation in vitro in bone marrow stromal cell cultures when COX-2 expression or activity (PG production) is absent. An inhibitory interaction between PTH and COX-2 is supported by in vivo data showing that COX-2 knockout (KO) mice have increased anabolic responses to intermittent PTH compared to COX-2 wild type (WT) mice. Preliminary studies in vitro suggest that the inhibitory effects of the interaction of PTH and COX-2 on OB differentiation require the presence of OC precursors and the expression of the PGE2 receptor EP4R on OC precursors. We will test the hypothesis that PTH-stimulated OB differentiation in vitro and PTH-stimulated anabolic responses in vivo are inhibited by PTH- induced PGs acting via the EP4R receptor on OC precursors. For both in vitro and in vivo studies, we will use mice with global and targeted deletions of Cox-2, Ep4r, and Ep2r. Deletions will be targeted to the early OC lineage with CD11b-Cre, to the later OC lineage with cathepsin K-Cre (CtskCre/+), and to the early OB lineage with 3.6Col1a1-Cre. We will use the pattern of gene expression in osteogenic vs. inhibitory conditions to identify potential pathways, such as Wnt signaling, associated with the osteogenic effects. In vivo, we will examine anabolic and catabolic responses to intermittent and continuous PTH with radiographic and histomorphometric measures of skeletal phenotype, markers of bone turnover, and gene expression. This study addresses a novel role for PGs and OCs in the effects of PTH. It is an opportunity to explore mechanisms by which two agents, both of which can be anabolic, produce a negative interaction, in an effort to understand the specific pathways involved. It should lead to a better understanding of the roles of endogenous PGs in both OB and OC lineage cells and the differential effects of PGE2 receptors, and this knowledge may help to target bone remodeling more effectively to treat osteoporosis and other skeletal defects. The possibility that manipulation of endogenous PGs might increase the anabolic effects of PTH could have clinical applications.

Public Health Relevance

PTH is a major calcium regulating hormone, and intermittent PTH is the only approved anabolic therapy for osteoporosis. The PTH-induction of prostaglandins can modulate the bone responses to PTH. A better understanding of the role of prostaglandins in the responses to PTH could have an important impact on our understanding of the mechanisms that drive new bone formation, laying the basis for future development of new agents to treat osteoporosis and other skeletal defects, and might also lead to applications that will enhance current clinical therapy with PTH.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR060286-03
Application #
8485547
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Chen, Faye H
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$329,175
Indirect Cost
$115,425
Name
University of Connecticut
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Deb Roy, Abhijit; Yin, Taofei; Choudhary, Shilpa et al. (2017) Optogenetic activation of Plexin-B1 reveals contact repulsion between osteoclasts and osteoblasts. Nat Commun 8:15831
Hewett, Sandra J; Shi, Jingxue; Gong, Yifan et al. (2016) Spontaneous Glutamatergic Synaptic Activity Regulates Constitutive COX-2 Expression in Neurons: OPPOSING ROLES FOR THE TRANSCRIPTION FACTORS CREB (cAMP RESPONSE ELEMENT BINDING) PROTEIN AND Sp1 (STIMULATORY PROTEIN-1). J Biol Chem 291:27279-27288
Choudhary, Shilpa; Goetjen, Alexandra; Estus, Thomas et al. (2016) Serum Amyloid A3 Secreted by Preosteoclasts Inhibits Parathyroid Hormone-stimulated cAMP Signaling in Murine Osteoblasts. J Biol Chem 291:3882-94
Estus, Thomas L; Choudhary, Shilpa; Pilbeam, Carol C (2016) Prostaglandin-mediated inhibition of PTH-stimulated ?-catenin signaling in osteoblasts by bone marrow macrophages. Bone 85:123-30
Choudhary, Shilpa; Canalis, Ernesto; Estus, Thomas et al. (2015) Cyclooxygenase-2 suppresses the anabolic response to PTH infusion in mice. PLoS One 10:e0120164
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Choudhary, Shilpa; Blackwell, Katherine; Voznesensky, Olga et al. (2013) Prostaglandin E2 acts via bone marrow macrophages to block PTH-stimulated osteoblast differentiation in vitro. Bone 56:31-41
Choudhary, Shilpa; Hegde, Poornima; Pruitt, James R et al. (2013) Macrophage migratory inhibitory factor promotes bladder cancer progression via increasing proliferation and angiogenesis. Carcinogenesis 34:2891-9
Xu, Manshan; Choudhary, Shilpa; Voznesensky, Olga et al. (2010) Basal bone phenotype and increased anabolic responses to intermittent parathyroid hormone in healthy male COX-2 knockout mice. Bone 47:341-52

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