Skip to main content
SpringerLink
Log in

Prostaglandins and Bone

  • Chapter
  • First Online:
Bone Regulators and Osteoporosis Therapy

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 262))

Abstract

Prostaglandins (PGs) are highly bioactive fatty acids. PGs, especially prostaglandin E2 (PGE2), are abundantly produced by cells of both the bone-forming (osteoblast) lineage and the bone-resorbing (osteoclast) lineage. The inducible cyclooxygenase, COX-2, is largely responsible for most PGE2 production in bone, and once released, PGE2 is rapidly degraded in vivo. COX-2 is induced by multiple agonists – hormones, growth factors, and proinflammatory factors – and the resulting PGE2 may mediate, amplify, or, as we have recently shown for parathyroid hormone (PTH), inhibit responses to these agonists. In vitro, PGE2 can directly stimulate osteoblast differentiation and, indirectly via stimulation of RANKL in osteoblastic cells, stimulate the differentiation of osteoclasts. The net balance of these two effects of PGE2 in vivo on bone formation and bone resorption has been hard to predict and, as expected for such a widespread local factor, hard to study. Some of the complexity of PGE2 actions on bone can be explained by the fact that there are four receptors for PGE2 (EP1–4). Some of the major actions of PGE2 in vitro occur via EP2 and EP4, both of which can stimulate cAMP signaling, but there are other distinct signaling pathways, important in other tissues, which have not yet been fully elucidated in bone cells. Giving PGE2 or agonists of EP2 and EP4 to accelerate bone repair has been examined with positive results. Further studies to clarify the pathways of PGE2 action in bone may allow us to identify new and more effective ways to deliver the therapeutic benefits of PGE2 in skeletal disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Alam I, Warden SJ, Robling AG, Turner CH (2005) Mechanotransduction in bone does not require a functional cyclooxygenase-2 (COX-2) gene. J Bone Miner Res 20:438–446

    CAS  PubMed  Google Scholar 

  • Alander CB, Raisz LG (2006) Effects of selective prostaglandin E2 receptor agonists on cultured calvarial murine osteoblastic cells. Prostaglandins Other Lipid Mediat 81:178–183

    CAS  PubMed  PubMed Central  Google Scholar 

  • Antczak MI, Zhang Y, Wang C, Doran J, Naidoo J, Voruganti S, Williams NS, Markowitz SD, Ready JM (2017) Inhibitors of 15-prostaglandin dehydrogenase to potentiate tissue repair. J Med Chem 60:3979–4001

    CAS  PubMed  PubMed Central  Google Scholar 

  • Augustine M, Horwitz MJ (2013) Parathyroid hormone and parathyroid hormone-related protein analogs as therapies for osteoporosis. Curr Osteoporos Rep 11:400–406

    PubMed  Google Scholar 

  • Blackwell KA, Raisz LG, Pilbeam CC (2010) Prostaglandins in bone: good cop? bad cop? Trends Endocrinol Metab 21:294–301

    CAS  PubMed  PubMed Central  Google Scholar 

  • Boyce BF, Xing L (2008) Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 473:139–146

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brown KM, Saunders MM, Kirsch T, Donahue HJ, Reid JS (2004) Effect of COX-2-specific inhibition on fracture-healing in the rat femur. J Bone Joint Surg Am 86-A:116–123

    Google Scholar 

  • Buchanan FG, DuBois RN (2006) Connecting COX-2 and Wnt in cancer. Cancer Cell 9:6–8

    CAS  PubMed  Google Scholar 

  • Buczynski MW, Dumlao DS, Dennis EA (2009) Thematic review series: proteomics. An integrated omics analysis of eicosanoid biology. J Lipid Res 50:1015–1038

    CAS  PubMed  PubMed Central  Google Scholar 

  • Castellone MD, Teramoto H, Gutkind JS (2006) Cyclooxygenase-2 and colorectal cancer chemoprevention: the beta-catenin connection. Cancer Res 66:11085–11088

    CAS  PubMed  Google Scholar 

  • Chen H, Hu B, Lv X, Zhu S, Zhen G, Wan M, Jain A, Gao B, Chai Y, Yang M, Wang X, Deng R, Wang L, Cao Y, Ni S, Liu S, Yuan W, Chen H, Dong X, Guan Y, Yang H, Cao X (2019) Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis. Nat Commun 10:181

    PubMed  PubMed Central  Google Scholar 

  • Chikazu D, Li X, Kawaguchi H, Sakuma Y, Voznesensky OS, Adams DJ, Xu M, Hoshi K, Katavic V, Herschman HR, Raisz LG, Pilbeam CC (2005) Bone morphogenetic protein 2 induces cyclooxygenase 2 in osteoblasts via a Cbfa1 binding site: role in effects of bone morphogenetic protein 2 in vitro and in vivo. 2002. J Bone Miner Res 20:1888–1898

    PubMed  Google Scholar 

  • Choudhary S, Wadhwa S, Raisz LG, Alander C, Pilbeam CC (2003) Extracellular calcium is a potent inducer of cyclooxygenase-2 in murine osteoblasts through an ERK signaling pathway. J Bone Miner Res 18:1813–1824

    CAS  PubMed  Google Scholar 

  • Choudhary S, Halbout P, Alander C, Raisz L, Pilbeam C (2007) Strontium ranelate promotes osteoblastic differentiation and mineralization of murine bone marrow stromal cells: involvement of prostaglandins. J Bone Miner Res 22:1002–1010

    CAS  PubMed  Google Scholar 

  • Choudhary S, Alander C, Zhan P, Gao Q, Pilbeam C, Raisz L (2008) Effect of deletion of the prostaglandin EP2 receptor on the anabolic response to prostaglandin E2 and a selective EP2 receptor agonist. Prostaglandins Other Lipid Mediat 86:35–40

    CAS  PubMed  PubMed Central  Google Scholar 

  • Choudhary S, Blackwell K, Voznesensky O, Deb RA, Pilbeam C (2013) Prostaglandin E2 acts via bone marrow macrophages to block PTH-stimulated osteoblast differentiation in vitro. Bone 56:31–41

    CAS  PubMed  PubMed Central  Google Scholar 

  • Choudhary S, Canalis E, Estus T, Adams D, Pilbeam C (2015) Cyclooxygenase-2 suppresses the anabolic response to PTH infusion in mice. PLoS One 10:e0120164

    PubMed  PubMed Central  Google Scholar 

  • Choudhary S, Goetjen A, Estus T, Jacome-Galarza CE, Aguila HL, Lorenzo J, Pilbeam C (2016) Serum amyloid A3 secreted by preosteoclasts inhibits parathyroid hormone-stimulated cAMP signaling in murine osteoblasts. J Biol Chem 291:3882–3894

    CAS  PubMed  Google Scholar 

  • Choudhary S, Santone E, Yee S-P, Lorenzo J, Adams DJ, Goetjen A, McCarthy MB, Mazzocca A, Pilbeam C (2018) Continuous PTH in mice causes bone loss because it induces serum amyloid A (SAA). Endocrinology 159:2759–2776

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dennis EA, Norris PC (2015) Eicosanoid storm in infection and inflammation. Nat Rev Immunol 15:511–523

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dennis EA, Cao J, Hsu YH, Magrioti V, Kokotos G (2011) Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem Rev 111:6130–6185

    CAS  PubMed  PubMed Central  Google Scholar 

  • Desai A, Zhang Y, Park Y, Dawson DM, Larusch GA, Kasturi L, Wald D, Ready JM, Gerson SL, Markowitz SD (2018) A second-generation 15-PGDH inhibitor promotes bone marrow transplant recovery independent of age, transplant dose, and G-CSF support. Haematologica 103:1054–1064

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dinchuk JE, Car BD, Focht RJ, Johnston JJ, Jaffee BD, Covington MB, Contel NR, Eng VM, Collins RJ, Czerniak PM (1995) Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature 378:406–409

    CAS  PubMed  Google Scholar 

  • Einhorn TA (2003) Cox-2: where are we in 2003? the role of cyclooxygenase-2 in bone repair. Arthritis Res Ther 5:5–7

    CAS  PubMed  Google Scholar 

  • Estus TL, Choudhary S, Pilbeam CC (2016) Prostaglandin-mediated inhibition of PTH-stimulated beta-catenin signaling in osteoblasts by bone marrow macrophages. Bone 85:123–130

    CAS  PubMed  PubMed Central  Google Scholar 

  • Faye-Petersen OM, Johnson WH Jr, Carlo WA, Hedlund GL, Pacifico AD, Blair HC (1996) Prostaglandin E1-induced hyperostosis: clinicopathologic correlations and possible pathogenetic mechanisms. Pediatr Pathol Lab Med 16:489–507

    CAS  PubMed  Google Scholar 

  • Ferreira SH, Vane JR (1967) Prostaglandins: their disappearance from and release into the circulation. Nature 216:868–873

    CAS  PubMed  Google Scholar 

  • Flanagan AM, Chambers TJ (1992) Stimulation of bone nodule formation in vitro by prostaglandins E1 and E2. Endocrinology 130:443–448

    CAS  PubMed  Google Scholar 

  • Fries S, Grosser T, Price TS, Lawson JA, Kapoor S, DeMarco S, Pletcher MT, Wiltshire T, Fitzgerald GA (2006) Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2. Gastroenterology 130:55–64

    CAS  PubMed  Google Scholar 

  • Gao Q, Zhan P, Alander CB, Kream BE, Hao C, Breyer MD, Pilbeam CC, Raisz LG (2009) Effects of global or targeted deletion of the EP4 receptor on the response of osteoblasts to prostaglandin in vitro and on bone histomorphometry in aged mice. Bone 45:98–103

    CAS  PubMed  Google Scholar 

  • Gerstenfeld LC, Al-Ghawas M, Alkhiary YM, Cullinane DM, Krall EA, Fitch JL, Webb EG, Thiede MA, Einhorn TA (2007) Selective and nonselective cyclooxygenase-2 inhibitors and experimental fracture-healing. Reversibility of effects after short-term treatment. J Bone Joint Surg Am 89:114–125

    CAS  PubMed  Google Scholar 

  • Geusens P, Emans PJ, de Jong JJ, van den Bergh J (2013) NSAIDs and fracture healing. Curr Opin Rheumatol 25:524–531

    CAS  PubMed  Google Scholar 

  • Grosser T, Ricciotti E, FitzGerald GA (2017a) The cardiovascular pharmacology of nonsteroidal anti-inflammatory drugs. Trends Pharmacol Sci 38:733–748

    CAS  PubMed  PubMed Central  Google Scholar 

  • Grosser T, Theken KN, FitzGerald GA (2017b) Cyclooxygenase inhibition: pain, inflammation, and the cardiovascular system. Clin Pharmacol Ther 102:611–622

    PubMed  Google Scholar 

  • Hara S (2017) Prostaglandin terminal synthases as novel therapeutic targets. Proc Jpn Acad Ser B Phys Biol Sci 93:703–723

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hara S, Kamei D, Sasaki Y, Tanemoto A, Nakatani Y, Murakami M (2010) Prostaglandin E synthases: understanding their pathophysiological roles through mouse genetic models. Biochimie 92:651–659

    CAS  PubMed  Google Scholar 

  • Herschman HR (1994) Regulation of prostaglandin synthase-1 and prostaglandin synthase-2. Cancer Metastasis Rev 13:241–256

    CAS  PubMed  Google Scholar 

  • Hino S, Tanji C, Nakayama KI, Kikuchi A (2005) Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes beta-catenin through inhibition of its ubiquitination. Mol Cell Biol 25:9063–9072

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang KC, Huang TW, Yang TY, Lee MS (2015) Chronic NSAIDs use increases the risk of a second hip fracture in patients after hip fracture surgery: evidence from a STROBE-compliant population-based study. Medicine (Baltimore) 94:e1566. https://doi.org/10.1097/MD.0000000000001566

    Article  CAS  Google Scholar 

  • Iida-Klein A, Lu SS, Kapadia R, Burkhart M, Moreno A, Dempster DW, Lindsay R (2005) Short-term continuous infusion of human parathyroid hormone 1-34 fragment is catabolic with decreased trabecular connectivity density accompanied by hypercalcemia in C57BL/J6 mice. J Endocrinol 186:549–557

    CAS  PubMed  Google Scholar 

  • Inoue H, Tanaka N, Uchiyama C (1995) Parathyroid hormone increases the number of tartrate-resistant acid phosphatase-positive cells through prostaglandin E2 synthesis in adherent cell culture of neonatal rat bones. Endocrinology 136:3648–3656

    CAS  PubMed  Google Scholar 

  • Janssen MP, Caron MM, van Rietbergen B, Surtel DA, van Rhijn LW, Welting TJ, Emans PJ (2017) Impairment of the chondrogenic phase of endochondral ossification in vivo by inhibition of cyclooxygenase-2. Eur Cell Mater 34:202–216

    CAS  PubMed  Google Scholar 

  • Jee WS, Ma YF (1997) The in vivo anabolic actions of prostaglandins in bone. Bone 21:297–304

    CAS  PubMed  Google Scholar 

  • Kang YJ, Mbonye UR, Delong CJ, Wada M, Smith WL (2007) Regulation of intracellular cyclooxygenase levels by gene transcription and protein degradation. Prog Lipid Res 46:108–125

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kawaguchi H, Raisz LG, Voznesensky OS, Alander CB, Hakeda Y, Pilbeam CC (1994) Regulation of the two prostaglandin G/H synthases by parathyroid hormone, interleukin-1, cortisol and prostaglandin E2 in cultured neonatal mouse calvariae. Endocrinology 135:1157–1164

    CAS  PubMed  Google Scholar 

  • Kawaguchi H, Pilbeam CC, Gronowicz G, Abreu C, Fletcher BS, Herschman HR, Raisz LG, Hurley MM (1995) Transcriptional induction of prostaglandin G/H synthase-2 by basic fibroblast growth factor. J Clin Invest 96:923–930

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kayani B, Sewell MD, Platinum J, Olivier A, Briggs TWR, Eastwood DM (2017) Orthopaedic manifestations of congenital indifference to pain with anhidrosis (hereditary sensory and autonomic neuropathy type IV). Eur J Paediatr Neurol 21:318–326

    PubMed  Google Scholar 

  • Kennedy BP, Payette P, Mudgett J, Vadas P, Pruzanski W, Kwan M, Tang C, Rancourt DE, Cromlish WA (1995) A natural disruption of the secretory group II phospholipase A2 gene in inbred mouse strains. J Biol Chem 270:22378–22385

    CAS  PubMed  Google Scholar 

  • Kirkby NS, Chan MV, Zaiss AK, Garcia-Vaz E, Jiao J, Berglund LM, Verdu EF, Ahmetaj-Shala B, Wallace JL, Herschman HR, Gomez MF, Mitchell JA (2016) Systematic study of constitutive cyclooxygenase-2 expression: role of NF-kappaB and NFAT transcriptional pathways. Proc Natl Acad Sci U S A 113:434–439

    CAS  PubMed  Google Scholar 

  • Klein DC, Raisz LG (1970) Prostaglandins: stimulation of bone resorption in tissue culture. Endocrinology 86:1436–1440

    CAS  PubMed  Google Scholar 

  • Klein-Nulend J, Burger EH, Semeins CM, Raisz LG, Pilbeam CC (1997) Pulsating fluid flow stimulates prostaglandin release and inducible prostaglandin G/H synthase mRNA expression in primary mouse bone cells. J Bone Miner Res 12:45–51

    CAS  PubMed  Google Scholar 

  • Konstantinidis I, Papageorgiou SN, Kyrgidis A, Tzellos TG, Kouvelas D (2013) Effect of non-steroidal anti-inflammatory drugs on bone turnover: an evidence-based review. Rev Recent Clin Trials 8:48–60

    CAS  PubMed  Google Scholar 

  • Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR (1991) TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 266:12866–12872

    CAS  PubMed  Google Scholar 

  • Kurmis AP, Kurmis TP, O’Brien JX, Dalen T (2012) The effect of nonsteroidal anti-inflammatory drug administration on acute phase fracture-healing: a review. J Bone Joint Surg Am 94:815–823

    PubMed  Google Scholar 

  • Lader CS, Flanagan AM (1998) Prostaglandin E2, interleukin 1alpha, and tumor necrosis factor-alpha increase human osteoclast formation and bone resorption in vitro. Endocrinology 139:3157–3164

    CAS  PubMed  Google Scholar 

  • Langenbach R, Morham SG, Tiano HF, Loftin CD, Ghanayem BI, Chulada PC, Mahler JF, Lee CA, Goulding EH, Kluckman KD (1995) Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 83:483–492

    CAS  PubMed  Google Scholar 

  • Langenbach R, Loftin C, Lee C, Tiano H (1999) Cyclooxygenase knockout mice: models for elucidating isoform-specific functions. Biochem Pharmacol 58:1237–1246

    CAS  PubMed  Google Scholar 

  • Leslie CC (2015) Cytosolic phospholipase A(2): physiological function and role in disease. J Lipid Res 56:1386–1402

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, McCabe S, Elliott R, Scully S, Van G, Kaufman S, Juan SC, Sun Y, Tarpley J, Martin L, Christensen K, McCabe J, Kostenuik P, Hsu H, Fletcher F, Dunstan CR, Lacey DL, Boyle WJ (2000) RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci U S A 97:1566–1571

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li M, Ke HZ, Qi H, Healy DR, Li Y, Crawford DT, Paralkar VM, Owen TA, Cameron KO, Lefker BA, Brown TA, Thompson DD (2003) A novel, non-prostanoid EP2 receptor-selective prostaglandin E2 agonist stimulates local bone formation and enhances fracture healing. J Bone Miner Res 18:2033–2042

    CAS  PubMed  Google Scholar 

  • Li M, Healy DR, Li Y, Simmons HA, Crawford DT, Ke HZ, Pan LC, Brown TA, Thompson DD (2005) Osteopenia and impaired fracture healing in aged EP4 receptor knockout mice. Bone 37:46–54

    CAS  PubMed  Google Scholar 

  • Li M, Thompson DD, Paralkar VM (2007) Prostaglandin E(2) receptors in bone formation. Int Orthop 31:767–772

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lim H, Paria BC, Das SK, Dinchuk JE, Langenbach R, Trzaskos JM, Dey SK (1997) Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell 91:197–208

    CAS  PubMed  Google Scholar 

  • Lin BY, Jee WSS, Ma YF, Ke HZ, Kimmel DB, Li XJ (1994) Effects of prostaglandin E2 and risedronate administration on cancellous bone in older female rats. Bone 15:489–496

    CAS  PubMed  Google Scholar 

  • Loftin CD, Trivedi DB, Tiano HF, Clark JA, Lee CA, Epstein JA, Morham SG, Breyer MD, Nguyen M, Hawkins BM, Goulet JL, Smithies O, Koller BH, Langenbach R (2001) Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2. Proc Natl Acad Sci U S A 98:1059–1064

    CAS  PubMed  PubMed Central  Google Scholar 

  • MacPhee M, Chepenik KP, Liddell RA, Nelson KK, Siracusa LD, Buchberg AM (1995) The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell 81:957–966

    CAS  PubMed  Google Scholar 

  • Mahon MJ (2012) The parathyroid hormone receptorsome and the potential for therapeutic intervention. Curr Drug Targets 13:116–128

    CAS  PubMed  Google Scholar 

  • Markovic T, Jakopin Z, Dolenc MS, Mlinaric-Rascan I (2017) Structural features of subtype-selective EP receptor modulators. Drug Discov Today 22:57–71

    CAS  PubMed  Google Scholar 

  • Marquez-Lara A, Hutchinson ID, Nunez F Jr, Smith TL, Miller AN (2016) Nonsteroidal anti-inflammatory drugs and bone-healing: a systematic review of research quality. JBJS Rev. https://doi.org/10.2106/JBJS.RVW.O.00055

  • Mbonye UR, Wada M, Rieke CJ, Tang HY, DeWitt DL, Smith WL (2006) The 19-amino acid cassette of cyclooxygenase-2 mediates entry of the protein into the endoplasmic reticulum-associated degradation system. J Biol Chem 281:35770–35778

    CAS  PubMed  Google Scholar 

  • Min YK, Rao Y, Okada Y, Raisz LG, Pilbeam CC (1998) Regulation of prostaglandin G/H synthase-2 expression by interleukin-1 in human osteoblast-like cells. J Bone Miner Res 13:1066–1075

    CAS  PubMed  Google Scholar 

  • Miyaura C, Inada M, Suzawa T, Sugimoto Y, Ushikubi F, Ichikawa A, Narumiya S, Suda T (2000) Impaired bone resorption to prostaglandin E2 in prostaglandin E receptor EP4-knockout mice. J Biol Chem 275:19819–19823

    CAS  PubMed  Google Scholar 

  • Morham SG, Langenbach R, Loftin CD, Tiano HF, Vouloumanos N, Jennette JC, Mahler JF, Kluckman KD, Ledford A, Lee CA (1995) Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell 83:473–482

    CAS  PubMed  Google Scholar 

  • Murakami M, Taketomi Y, Miki Y, Sato H, Hirabayashi T, Yamamoto K (2011) Recent progress in phospholipase A(2) research: from cells to animals to humans. Prog Lipid Res 50:152–192

    CAS  PubMed  Google Scholar 

  • Murakami M, Sato H, Miki Y, Yamamoto K, Taketomi Y (2015) A new era of secreted phospholipase A(2). J Lipid Res 56:1248–1261

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nahorski MS, Chen YC, Woods CG (2015) New Mendelian disorders of painlessness. Trends Neurosci 38:712–724

    CAS  PubMed  Google Scholar 

  • Norrdin RW, Shih MS (1988) Systemic effects of prostaglandin E2 on vertebral trabecular remodeling in beagles used in a healing study. Calcif Tissue Int 42:363–368

    CAS  PubMed  Google Scholar 

  • Norwood VF, Morham SG, Smithies O (2000) Postnatal development and progression of renal dysplasia in cyclooxygenase-2 null mice. Kidney Int 58:2291–2300

    CAS  PubMed  Google Scholar 

  • O’Banion MK, Sadowski HB, Winn V, Young DA (1991) A serum- and glucorticoid-regulated 4-kilobase mRNA encodes a cyclooxygenase-related protein. J Biol Chem 266:23261–23267

    PubMed  Google Scholar 

  • O’Callaghan G, Houston A (2015) Prostaglandin E2 and the EP receptors in malignancy: possible therapeutic targets? Br J Pharmacol 172:5239–5250

    PubMed  PubMed Central  Google Scholar 

  • O’Connor JP, Manigrasso MB, Kim BD, Subramanian S (2014) Fracture healing and lipid mediators. Bonekey Rep 3:517. https://doi.org/10.1038/bonekey.2014.12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okada Y, Lorenzo JA, Freeman AM, Tomita M, Morham SG, Raisz LG, Pilbeam CC (2000a) Prostaglandin G/H synthase-2 is required for maximal formation of osteoclast-like cells in culture. J Clin Invest 105:823–832

    CAS  PubMed  PubMed Central  Google Scholar 

  • Okada Y, Tomita M, Gronowicz G, Kawaguchi H, Sohn J, Tanaka Y, Morimoto I, Nakamura T, Raisz L, Pilbeam C (2000b) Effects of cyclooxygenase-2 gene disruption on osteoblastic function. J Bone Miner Res 15:S217

    Google Scholar 

  • Paralkar VM, Borovecki F, Ke HZ, Cameron KO, Lefker B, Grasser WA, Owen TA, Li M, Silva-Jardine P, Zhou M, Dunn RL, Dumont F, Korsmeyer R, Krasney P, Brown TA, Plowchalk D, Vukicevic S, Thompson DD (2003) An EP2 receptor-selective prostaglandin E2 agonist induces bone healing. Proc Natl Acad Sci U S A 100:6736–6740

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pavalko FM, Chen NX, Turner CH, Burr DB, Atkinson S, Hsieh YF, Qiu J, Duncan RL (1998) Fluid shear-induced mechanical signaling in MC3T3-E1 osteoblasts requires cytoskeleton-integrin interactions. Am J Physiol 275:C1591–C1601

    CAS  PubMed  Google Scholar 

  • Phatarakijnirund V, Mumm S, McAlister WH, Novack DV, Wenkert D, Clements KL, Whyte MP (2016) Congenital insensitivity to pain: fracturing without apparent skeletal pathobiology caused by an autosomal dominant, second mutation in SCN11A encoding voltage-gated sodium channel 1.9. Bone 84:289–298

    CAS  PubMed  Google Scholar 

  • Pilbeam CC, Kawaguchi H, Hakeda Y, Voznesensky O, Alander CB, Raisz LG (1993) Differential regulation of inducible and constitutive prostaglandin endoperoxide synthase in osteoblastic MC3T3-E1 cells. J Biol Chem 268:25643–25649

    CAS  PubMed  Google Scholar 

  • Pilbeam CC, Raisz LG, Voznesensky O, Alander CB, Delman BN, Kawaguchi K (1994) Autoregulation of inducible prostaglandin G/H synthase in osteoblastic cells by prostaglandins. J Bone Miner Res 10:406–414

    Google Scholar 

  • Pilbeam C, Rao Y, Voznesensky O, Kawaguchi H, Alander C, Raisz LG, Herschman H (1997) Transforming growth factor-β1 regulation of prostaglandin G/H syntase-2 expression in osteoblastic MC3T3-E1 cells. Endocrinology 138:4672–4682

    CAS  PubMed  Google Scholar 

  • Pilbeam CC, Choudhary S, Blackwell KA, Raisz LG (2008) Prostaglandins and bone metabolism. In: Bilezikian JP, Raisz LG, Martn TJ (eds) Principles of bone biology, 3rd edn. Elsevier/Academic Press, San Diego

    Google Scholar 

  • Potts JT, Gardella TJ (2007) Progress, paradox, and potential: parathyroid hormone research over five decades. Ann N Y Acad Sci 1117:196–208

    CAS  PubMed  Google Scholar 

  • Pountos I, Georgouli T, Calori GM, Giannoudis PV (2012) Do nonsteroidal anti-inflammatory drugs affect bone healing? A critical analysis. ScientificWorldJournal 2012:606404. https://doi.org/10.1100/2012/606404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Psarra A, Nikolaou A, Kokotou MG, Limnios D, Kokotos G (2017) Microsomal prostaglandin E2 synthase-1 inhibitors: a patent review. Expert Opin Ther Pat 27:1047–1059

    CAS  PubMed  Google Scholar 

  • Raisz LG, Woodiel FN (2003) Effects of selective prostaglandin EP2 and EP4 receptor agonists on bone resorption and formation in fetal rat organ cultures. Prostaglandins Other Lipid Mediat 71:287–292

    CAS  PubMed  Google Scholar 

  • Richards JB, Joseph L, Schwartzman K, Kreiger N, Tenenhouse A, Goltzman D (2006) The effect of cyclooxygenase-2 inhibitors on bone mineral density: results from the Canadian Multicentre Osteoporosis Study. Osteoporos Int 17:1410–1419

    CAS  PubMed  Google Scholar 

  • Robertson G, Xie C, Chen D, Awad H, Schwarz EM, O’Keefe RJ, Guldberg RE, Zhang X (2006) Alteration of femoral bone morphology and density in COX-2-/- mice. Bone 39:767–772

    CAS  PubMed  PubMed Central  Google Scholar 

  • Robling AG, Kedlaya R, Ellis SN, Childress PJ, Bidwell JP, Bellido T, Turner CH (2011) Anabolic and catabolic regimens of human parathyroid hormone 1-34 elicit bone- and envelope-specific attenuation of skeletal effects in Sost-deficient mice. Endocrinology 152:2963–2975

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sagi HC, Jordan CJ, Barei DP, Serrano-Riera R, Steverson B (2014) Indomethacin prophylaxis for heterotopic ossification after acetabular fracture surgery increases the risk for nonunion of the posterior wall. J Orthop Trauma 28:377–383

    PubMed  Google Scholar 

  • Sato T, Morita I, Sakaguchi K, Nakahama KI, Smith WL, DeWitt DL, Murota SI (1996) Involvement of prostaglandin endoperoxide H synthase-2 in osteoclast-like cell formation induced by interleukin-1 beta. J Bone Miner Res 11:392–400

    CAS  PubMed  Google Scholar 

  • Segi E, Sugimoto Y, Yamasaki A, Aze Y, Oida H, Nishimura T, Murata T, Matsuoka T, Ushikubi F, Hirose M, Tanaka T, Yoshida N, Narumiya S, Ichikawa A (1998) Patent ductus arteriosus and neonatal death in prostaglandin receptor EP4-deficient mice. Biochem Biophys Res Commun 246:7–12

    CAS  PubMed  Google Scholar 

  • Shao J, Jung C, Liu C, Sheng H (2005) Prostaglandin E2 stimulates the beta-catenin/T cell factor-dependent transcription in colon cancer. J Biol Chem 280:26565–26572

    CAS  PubMed  Google Scholar 

  • Simmons DL, Botting RM, Hla T (2004) Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 56:387–437

    CAS  PubMed  Google Scholar 

  • Simon AM, O’Connor JP (2007) Dose and time-dependent effects of cyclooxygenase-2 inhibition on fracture-healing. J Bone Joint Surg Am 89:500–511

    PubMed  Google Scholar 

  • Sivaganesan A, Chotai S, White-Dzuro G, McGirt MJ, Devin CJ (2017) The effect of NSAIDs on spinal fusion: a cross-disciplinary review of biochemical, animal, and human studies. Eur Spine J 26:2719–2728

    PubMed  Google Scholar 

  • Smith WL, Langenbach R (2001) Why there are two cyclooxygenase isozymes. J Clin Invest 107:1491–1495

    CAS  PubMed  PubMed Central  Google Scholar 

  • Smith WL, DeWitt DL, Garavito RM (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69:145–182

    CAS  PubMed  Google Scholar 

  • Smith WL, Urade Y, Jakobsson PJ (2011) Enzymes of the cyclooxygenase pathways of prostanoid biosynthesis. Chem Rev 111:5821–5865

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sugimoto Y, Narumiya S (2007) Prostaglandin E receptors. J Biol Chem 282:11613–11617

    CAS  PubMed  Google Scholar 

  • Suponitzky I, Weinreb M (1998) Differential effects of systemic prostaglandin E2 on bone mass in rat long bones and calvariae. J Endocrinol 156:51–57

    CAS  PubMed  Google Scholar 

  • Suzawa T, Miyaura C, Inada M, Maruyama T, Sugimoto Y, Ushikubi F, Ichikawa A, Narumiya S, Suda T (2000) The role of prostaglandin E receptor subtypes (EP1, EP2, EP3, and EP4) in bone resorption: an analysis using specific agonists for the respective EPs. Endocrinology 141:1554–1559

    CAS  PubMed  Google Scholar 

  • Swinney DC, Mak AY, Barnett J, Ramesha CS (1997) Differential allosteric regulation of prostaglandin H synthase 1 and 2 by arachidonic acid. J Biol Chem 272:12393–12398

    CAS  PubMed  Google Scholar 

  • Tai H, Miyaura C, Pilbeam CC, Tamura T, Ohsugi Y, Koishihara Y, Kubodera N, Kawaguchi H, Raisz LG, Suda T (1997) Transcriptional induction of cyclooxygenase-2 in osteoblasts is involved in interleukin-6-induced osteoclast formation. Endocrinology 138:2372–2379

    CAS  PubMed  Google Scholar 

  • Tanaka M, Sakai A, Uchida S, Tanaka S, Nagashima M, Katayama T, Yamaguchi K, Nakamura T (2004) Prostaglandin E2 receptor (EP4) selective agonist (ONO-4819.CD) accelerates bone repair of femoral cortex after drill-hole injury associated with local upregulation of bone turnover in mature rats. Bone 34:940–948

    CAS  PubMed  Google Scholar 

  • Tang CH, Yang RS, Fu WM (2005) Prostaglandin E2 stimulates fibronectin expression through EP1 receptor, phospholipase C, protein kinase Calpha, and c-Src pathway in primary cultured rat osteoblasts. J Biol Chem 280:22907–22916

    CAS  PubMed  Google Scholar 

  • Tanioka T, Nakatani Y, Semmyo N, Murakami M, Kudo I (2000) Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis. J Biol Chem 275:32775–32782

    CAS  PubMed  Google Scholar 

  • Ueda K, Saito A, Nakano H, Aoshima M, Yokota M, Muraoka R, Iwaya T (1980) Cortical hyperostosis following long-term administration of prostaglandin E1 in infants with cyanotic congenital heart disease. J Pediatr 97:834–836

    CAS  PubMed  Google Scholar 

  • Uppal S, Diggle CP, Carr IM, Fishwick CW, Ahmed M, Ibrahim GH, Helliwell PS, Latos-Bielenska A, Phillips SE, Markham AF, Bennett CP, Bonthron DT (2008) Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nat Genet 40:789–793

    CAS  PubMed  Google Scholar 

  • Vasquez AM, Mouchlis VD, Dennis EA (2017) Review of four major distinct types of human phospholipase A2. Adv Biol Regul 10. https://doi.org/10.1016/j.jbior.2017.10.009

  • Vilardaga JP, Romero G, Friedman PA, Gardella TJ (2011) Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm. Cell Mol Life Sci 68:1–13

    CAS  PubMed  Google Scholar 

  • Wadhwa S, Choudhary S, Voznesensky M, Epstein M, Raisz L, Pilbeam C (2002) Fluid flow induces COX-2 expression in MC3T3-E1 osteoblasts via a PKA signaling pathway. Biochem Biophys Res Commun 297:46–51

    CAS  PubMed  Google Scholar 

  • Woodward DF, Jones RL, Narumiya S (2011) International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress. Pharmacol Rev 63:471–538

    CAS  PubMed  Google Scholar 

  • Xie WL, Chipman JG, Robertson DL, Erikson RL, Simmons DL (1991) Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci U S A 88:2692–2696

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xu M, Choudhary S, Goltzman D, Ledgard F, Adams D, Gronowicz G, Koczon-Jaremko B, Raisz L, Pilbeam C (2005) Do cyclooxygenase knockout mice have primary hyperparathyroidism? Endocrinology 146:1843–1853

    CAS  PubMed  Google Scholar 

  • Xu Z, Choudhary S, Okada Y, Voznesensky O, Alander C, Raisz L, Pilbeam C (2007) Cyclooxygenase-2 gene disruption promotes proliferation of murine calvarial osteoblasts in vitro. Bone 41:68–76

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xu M, Choudhary S, Voznesensky O, Gao Q, Adams D, Diaz-Doran V, Wu Q, Goltzman D, Raisz LG, Pilbeam CC (2010) Basal bone phenotype and increased anabolic responses to intermittent parathyroid hormone in healthy male COX-2 knockout mice. Bone 47:341–352

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshida K, Oida H, Kobayashi T, Maruyama T, Tanaka M, Katayama T, Yamaguchi K, Segi E, Tsuboyama T, Matsushita M, Ito K, Ito Y, Sugimoto Y, Ushikubi F, Ohuchida S, Kondo K, Nakamura T, Narumiya S (2002) Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation. Proc Natl Acad Sci U S A 99:4580–4585

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yuan C, Smith WL (2015) A cyclooxygenase-2-dependent prostaglandin E2 biosynthetic system in the Golgi apparatus. J Biol Chem 290:5606–5620

    CAS  PubMed  Google Scholar 

  • Zhan P, Alander C, Kaneko H, Pilbeam CC, Guan Y, Zhang Y, Breyer MD, Raisz LG (2005) Effect of deletion of the prostaglandin EP4 receptor on stimulation of calcium release from cultured mouse calvariae: impaired responsiveness in heterozygotes. Prostaglandins Other Lipid Mediat 78:19–26

    CAS  PubMed  Google Scholar 

  • Zhang Y, Haga N (2014) Skeletal complications in congenital insensitivity to pain with anhidrosis: a case series of 14 patients and review of articles published in Japanese. J Orthop Sci 19:827–831

    PubMed  Google Scholar 

  • Zhang X, Schwarz EM, Young DA, Puzas JE, Rosier RN, O’Keefe RJ (2002) Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest 109:1405–1415

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang M, Ho HC, Sheu TJ, Breyer MD, Flick LM, Jonason JH, Awad HA, Schwarz EM, O’Keefe RJ (2011) EP1(−/−) mice have enhanced osteoblast differentiation and accelerated fracture repair. J Bone Miner Res 26:792–802

    CAS  PubMed  Google Scholar 

  • Zhang M, Feigenson M, Sheu TJ, Awad HA, Schwarz EM, Jonason JH, Loiselle AE, O’Keefe RJ (2015a) Loss of the PGE2 receptor EP1 enhances bone acquisition, which protects against age and ovariectomy-induced impairments in bone strength. Bone 72:92–100

    CAS  PubMed  Google Scholar 

  • Zhang Y, Desai A, Yang SY, Bae KB, Antczak MI, Fink SP, Tiwari S, Willis JE, Williams NS, Dawson DM, Wald D, Chen WD, Wang Z, Kasturi L, Larusch GA, He L, Cominelli F, Di ML, Djuric Z, Milne GL, Chance M, Sanabria J, Dealwis C, Mikkola D, Naidoo J, Wei S, Tai HH, Gerson SL, Ready JM, Posner B, Willson JK, Markowitz SD (2015b) Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration. Science 348:aaa2340

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This effort was supported by National Institute of Health Grants NIAMS award AR060286.

Author information

Authors and Affiliations

  1. Department of Medicine and Musculoskeletal Institute, UConn Health, Farmington, CT, USA

    Carol Pilbeam

Authors
  1. Carol Pilbeam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carol Pilbeam .

Editor information

Editors and Affiliations

  1. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Paula H. Stern

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Pilbeam, C. (2019). Prostaglandins and Bone. In: Stern, P.H. (eds) Bone Regulators and Osteoporosis Therapy. Handbook of Experimental Pharmacology, vol 262. Springer, Cham. https://doi.org/10.1007/164_2019_332

Download citation

Publish with us

Policies and ethics

Search

Navigation