Parathyroid hormone–related peptide (PTHrP), parathyroid hormone/parathyroid hormone–related peptide receptor 1 (PTHR1), and MSX1 protein are expressed in central and peripheral giant cell granulomas of the jaws

Published:January 11, 2010DOI:


      Parathyroid hormone–related peptide (PTHrP) binds to the parathyroid hormone receptor type 1 (PTHR1), which results in the activation of pathways in osteoblasts that promote osteoclastogenesis through the RANK/RANKL system. RANK/RANKL expression has been shown in central giant cell granuloma of the jaws but PTHrP/PTHR1 has not. MSX1 protein is a classical transcription regulator which promotes cell proliferation and inhibits cell differentiation by inhibiting master genes in tissues such as bone and muscle. It has been implicated in the pathogenesis of cherubism, and its expression has been reported in a single central giant cell granuloma (CGCG) case. We aimed, therefore, to study the expression of those proteins by the different cellular populations of central and peripheral giant cell granulomas (PGCGs) of the jaws.

      Study design

      Twenty cases of CGCG and 20 cases of PGCG of the jaws were retrospectively examined by immunohistochemistry for the percentage of positively staining cells to antibodies for PTHrP, PTHR1, and MSX1, using a semiquantitative method.


      In both CGCG and PGCG of the jaws, PTHrP and PTHR1 were abundantly expressed by type I multinucleated giant cells (MGC) and mononucleated stromal cells (MSC) with vesicular nuclei, whereas type II MGC and MSC with pyknotic nuclei expressed those proteins to a lesser extent. In both CGCG and PGCG of the jaws, MSX1 was abundantly expressed by type I MGC and MSC but type II MGC did not express it. A statistically significant difference (P < .05) was observed between CGCG and PGCG in the expression of PTHrP in type II MGC and MSC with pyknotic nuclei and in the expression of PTHR1 in type II MGC.


      We suggest that in CGCG and PGCG of the jaws, PTHrP-positive immature osteoblasts activate PTHR1-positive mature osteoblasts to produce RANKL which interacts with RANK on the PTHrP/PTHR1-positive osteoclast-precursor cells found in abundance in the stroma of giant cell lesions and induces osteoclastogenesis through the classic pathway. Cells of the jawbones, the periodontal ligament, or the dental follicle, originating from the neural crest, may be involved in the pathogenesis of giant cell lesions of the jaws. Further study is required for these suggestions to be proved.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


        • Kramer I.R.H.
        • Pindborg J.J.
        • Shear M.
        Histological typing of odontogenic tumours.
        2nd ed. Springer-Verlag, Berlin1991 (p. 31)
        • Katsikeris N.
        • Kakarantza-Angelopoulou E.
        • Angelopoulos A.P.
        Peripheral giant cell granuloma.
        Int J Oral Maxillofac Surg. 1988; 17: 94-99
        • Sidhu M.S.
        • Parkash H.
        • Sidhu S.S.
        Central giant cell granuloma of jaws—review of 19 cases.
        Br J Oral Maxillofac Surg. 1995; 33: 43-46
        • Kruse-Losler B.
        • Diallo R.
        • Gaertner C.
        • Mischke K.L.
        • Joos U.
        • Kleinheinz J.
        Central giant cell granuloma of the jaws.
        Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006; : 346-354
        • Bodner L.
        • Peist M.
        • Gatot A.
        • Fliss D.M.
        Growth potential of peripheral giant cell granuloma.
        Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997; : 548-551
        • Philbrick W.M.
        • Wysolmerski J.J.
        • Galbraith S.
        • Holt E.
        • Orloff J.J.
        • Yang K.H.
        • et al.
        Defining the roles of parathyroid hormone-related protein in normal physiology.
        Physiol Rev. 1996; 76: 127-173
        • Burtis W.J.
        • Brady T.G.
        • Orloff J.J.
        • Ersbak J.B.
        • Warrell Jr, R.P.
        • Olson B.R.
        • et al.
        Immunochemical characterization of circulating parathyroid hormone–related protein in patients with humoral hypercalcemia of cancer.
        N Engl J Med. 1990; 322: 1106-1112
        • Broadus A.
        • Stewart A.
        Parathyroid hormone-reIated protein: structure, processing and physioIogic actions.
        in: Bilezikian J. The parathyroids: basic and clinical concepts. Raven Press, New York1994: 259-294
        • Juppner H.
        Receptors for parathyroid hormone and parathyroid hormone-related peptide: exploration of their biological importance.
        Bone. 1999; 25: 87-90
        • Swarthout J.
        • D'Alonzo R.
        • Selvamurugan N.
        • Partridge N.
        Parathyroid hormone–dependent signaling pathways regulating genes in bone cells.
        Gene. 2002; 282: 1-17
        • Huang J.
        • Sakata T.
        • Pfleger L.
        • Bencsik M.
        • Halloran B.
        • Bikle D.
        • et al.
        PTH differentially regulates expression of RANKL and OPG.
        J Bone Miner Res. 2004; 19: 235-244
        • Hofbauer L.C.
        • Schoppet M.
        Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases.
        JAMA. 2004; 292: 490-495
        • Lerner U.
        New molecules in the tumor necrosis factor ligand and receptor superfamilies with importance for physiological and pathological bone resorption.
        Crit Rev Oral Biol Med. 2004; 15: 64-81
        • Itonaga I.
        • Hussein I.
        • Kudo O.
        • Sabokbar A.
        • Watt-Smith S.
        • Ferguson D.
        • et al.
        Cellular mechanisms of osteoclast formation and lacunar resorption in giant cell granuloma of the jaw.
        J Oral Pathol Med. 2003; 32: 224-231
        • Liu B.
        • Yu S.F.
        • Li T.J.
        Multinucleated giant cells in various forms of giant cell containing lesions of the jaws express features of osteoclasts.
        J Oral Pathol Med. 2003; 32: 367-375
        • Nakashima M.
        • Ito M.
        • Ohtsuru A.
        • Alipov G.K.
        • Matsuzaki S.
        • Nakayama T.
        • et al.
        Expression of parathyroid hormone (PTH)–related peptide (PTHrP) and PTH/PTHrP receptor in giant cell tumour of tendon sheath.
        J Pathol. 1996; 180: 80-84
        • Nakashima M.
        • Nakayama T.
        • Ohtsuru A.
        • Fukada E.
        • Niino D.
        • Yamazumi K.
        • et al.
        Expression of parathyroid hormone (PTH)–related peptide (PTHrP) and PTH/PTHrP receptor in osteoclast-like giant cells.
        Pathol Res Pract. 2003; 199: 85-92
        • Hill R.E.
        • Jones P.F.
        • Rees A.R.
        • Sime C.M.
        • Justice M.J.
        • Copeland N.G.
        • et al.
        A new family of mouse homeo box–containing genes: molecular structure, chromosomal location, and developmental expression of HOX-7.1.
        Genes Dev. 1989; 3: 26-37
        • Ivens A.
        • Flavin N.
        • Williamson R.
        • Dixon M.
        • Bates G.
        • Buckingham M.
        • et al.
        The human homeobox gene HOX7 maps to chromosome 4p16.1 and may be implicated in Wolf-Hirschhorn syndrome.
        Hum Genet. 1990; 84: 473-476
        • Blin-Wakkach C.
        • Lezot F.
        • Ghoul-Mazgar S.
        • Hotton D.
        • Monteiro S.
        • Teillaud C.
        • et al.
        Endogenous MSX1 antisense transcript: in vivo and in vitro evidences, structure, and potential involvement in skeleton development in mammals.
        Proc Natl Acad Sci U S A. 2001; 98: 7336-7341
        • Odelberg S.J.
        • Kollhoff A.
        • Keating M.T.
        Dedifferentiation of mammalian myotubes induced by MSX1.
        Cell. 2000; 103: 1099-1109
        • Davidson D.
        The function and evolution of MSX genes: pointers and paradoxes.
        Trends Genet. 1995; 11: 405-411
        • Houzelstein D.
        • Auda-Boucher G.
        • Cheraud Y.
        • Rouaud T.
        • Blanc I.
        • Tajbakhsh S.
        • et al.
        The homeobox gene MSX1 is expressed in a subset of somites, and in muscle progenitor cells migrating into the forelimb.
        Development. 1999; 126: 2689-2701
        • Hyckel P.
        • Berndt A.
        • Schleier P.
        • Clement J.H.
        • Beensen V.
        • Peters H.
        • et al.
        Cherubism—new hypotheses on pathogenesis and therapeutic consequences.
        J Cran-Maxillofac Surg. 2005; 33: 61-68
        • Ueki Y.
        • Tiziani V.
        • Santanna C.
        • Fukai N.
        • Maulik C.
        • Garfinkle J.
        • et al.
        Mutations in the gene encoding c-Abl–binding protein SH3BP2 cause cherubism.
        Nat Genet. 2001; 28: 125-126
        • Vered M.
        • Buchner A.
        • Dayan D.
        Giant cell granuloma of the jawbones—a proliferative vascular lesion?.
        J Oral Pathol Med. 2006; 35: 613-619
        • Vered M.
        • Buchner A.
        • Dayan D.
        Immunohistochemical expression of glucocorticoid and calcitonin receptors as a tool for selecting therapeutic approach in central giant cell granuloma of the jawbones.
        Int J Oral Maxillofac Surg. 2006; 35: 756-760
        • Ishikawa M.
        • Ouchi Y.
        • Akishita M.
        • Kozaki K.
        • Toba K.
        • Namiki A.
        • et al.
        Immunocytochemical detection of parathyroid hormone–related protein in vascular endothelial cells.
        Biochem Biophys Res Commun. 1994; 199: 547-551
        • Rian E.
        • Jemtland R.
        • Olstad O.K.
        • Endresen M.J.
        • Grasser W.A.
        • Thiede M.A.
        • et al.
        Parathyroid hormone-related protein is produced by cultured endothelial cells: a possible role in angiogenesis.
        Biochem Biophys Res Commun. 1994; 198: 740-747
        • Naito S.
        • Shimizu K.
        • Akino K.
        • Ohtsuru A.
        • Watanabe M.
        • Yamashita S.
        • et al.
        Autocrine/paracrine involvement of parathyroid hormone–related peptide in vascular leiomyoma.
        Endocr J. 2002; 49: 335-341
        • Atillasoy E.J.
        • Burtis W.J.
        • Milstone L.M.
        • Atillasoy E.J.
        • Burtis W.J.
        • Milstone L.M.
        Immunohistochemical localization of parathyroid hormone-related protein (PTHRP) in normal human skin.
        J Invest Dermatol. 1991; 96 ([see comment]): 277-280
        • Seidel J.
        • Zabel M.
        • Kasprzak A.
        • Seidel J.
        • Zabel M.
        • Kasprzak A.
        PTHrP and cytokeratins in human epidermis.
        Folia Histochem Cytobiol. 2002; 40: 209-210
        • Kartsogiannis V.
        • Udagawa N.
        • Ng K.
        • Martin T.
        • Moseley J.
        • Zhou H.
        Localization of parathyroid hormone-related protein in osteoclasts by in situ hybridization and immunohistochemistry.
        Bone. 1998; 22: 189-194
        • Faucheux C.
        • Horton M.A.
        • Price J.S.
        Nuclear localization of type I parathyroid hormone/parathyroid hormone–related protein receptors in deer antler osteoclasts: evidence for parathyroid hormone–related protein and receptor activator of NF-kappaB–dependent effects on osteoclast formation in regenerating mammalian bone.
        J Bone Miner Res. 2002; 17: 455-464
        • Agarwala N.
        • Gay C.V.
        Specific binding of parathyroid hormone to living osteoclasts.
        J Bone Miner Res. 1992; 7: 531-539
        • Jiang B.
        • Morimoto S.
        • Yang J.
        • Niinoabu T.
        • Fukuo K.
        • Ogihara T.
        • et al.
        Expression of parathyroid hormone/parathyroid hormone–related protein receptor in vascular endothelial cells.
        J Cardiovasc Pharmacol. 1998; 31: S142-S144
        • Diamond A.G.
        • Gonterman R.M.
        • Anderson A.L.
        • Menon K.
        • Offutt C.D.
        • Weaver C.H.
        • et al.
        Parathyroid hormone hormone–related protein and the PTH receptor regulate angiogenesis of the skin.
        J Invest Dermatol. 2006; 126: 2127-2134
        • Wang Y.
        • Yang S.X.
        • Tu P.
        • Zhang B.
        • Ma S.Q.
        Expression of parathyroid hormone (PTH)/PTH–related peptide receptor messenger ribonucleic acid in mice hair cycle.
        J Dermatol Sci. 2002; 30: 136-141
        • Stelnicki E.
        • Kömüves L.
        • Holmes D.
        • Clavin W.
        • Harrison M.
        • Adzick N.
        • et al.
        The human homeobox genes MSX-1, MSX-2, and MOX-1 are differentially expressed in the dermis and epidermis in fetal and adult skin.
        Differentiation. 1997; 62: 33-41
        • Harris M.
        Central giant cell granulomas of the jaws regress with calcitonin therapy.
        Br J Oral Maxillofac Surg. 1993; 31: 89-94
        • Rao L.G.
        • Murray T.M.
        • Heersche J.N.
        Immunohistochemical demonstration of parathyroid hormone binding to specific cell types in fixed rat bone tissue.
        Endocrinology. 1983; 113: 805-810
        • Teti A.
        • Rizzoli R.
        • Zambonin Zallone A.
        Parathyroid hormone binding to cultured avian osteoclasts.
        Biochem Biophys Res Commun. 1991; 174: 1217-1222
        • Gay C.V.
        • Zheng B.
        • Gilman V.R.
        Co-detection of PTH/PTHrP receptor and tartrate resistant acid phosphatase in osteoclasts.
        J Cell Biochem. 2003; 89: 902-908
        • Langub M.C.
        • Monier-Faugere M.C.
        • Qi Q.
        • Geng Z.
        • Koszewski N.J.
        • Malluche H.H.
        Parathyroid hormone/parathyroid hormone–related peptide type 1 receptor in human bone.
        J Bone Miner Res. 2001; 16: 448-456
        • Dempster D.W.
        • Hughes-Begos C.E.
        • Plavetic-Chee K.
        • Brandao-Burch A.
        • Cosman F.
        • Nieves J.
        • et al.
        Normal human osteoclasts formed from peripheral blood monocytes express PTH type 1 receptors and are stimulated by PTH in the absence of osteoblasts.
        J Cell Biochem. 2005; 95: 139-148
        • Rodan G.A.
        • Martin T.J.
        Role of osteoblasts in hormonal control of bone resorption—a hypothesis.
        Calcif Tissue Int. 1981; 33: 349-351
        • Flanagan A.M.
        • Tinkler S.M.B.
        • Horton M.A.
        • Williams D.M.
        • Chambers T.J.
        The multinucleate cells in giant cell granulomas of the jaw are osteoclasts.
        Cancer. 1988; 62: 1139-1145
        • Vered M.
        • Buchner A.
        • Dayan D.
        Central giant cell granuloma of the jawbones—new insights into molecular biology with clinical implications on treatment approaches.
        Histol Histopathol. 2008; 23: 1151-1160
        • Vered M.
        • Nasrallah W.
        • Buchner A.
        • Dayan D.
        Stromal myofibroblasts in central giant cell granuloma of the jaws cannot distinguish between nonaggressive and aggressive lesions.
        J Oral Pathol Med. 2007; 36: 495-500
        • Carvalho Y.R.
        • Loyola A.M.
        • Gomez R.S.
        • Araujo V.C.
        Peripheral giant cell granuloma.
        Oral Dis. 1995; 1: 20-25
        • Regezi J.A.
        Comments on the pathogenesis and medical treatment of central giant cell granulomas.
        J Oral Maxillofac Surg. 2004; 62: 116-118
        • O'Malley M.
        • Pogrel M.A.
        • Stewart J.C.
        • Silva R.G.
        • Regezi J.A.
        Central giant cell granulomas of the jaws: phenotype and proliferation-associated markers.
        J Oral Pathol Med. 1997; 26: 159-163
        • de Souza P.E.A.
        • Paim J.F.O.
        • Carvalhais J.N.
        • Gomez R.S.
        Immunohistochemical expression of p53, MDM2, Ki-67, and PCNA in central giant cell granuloma and giant cell tumor.
        J Oral Pathol Med. 1999; 28: 54-58
        • Kauzman A.
        • Li S.Q.
        • Bradley G.
        • Bell R.S.
        • Wunder J.S.
        • Kandel R.
        Central giant cell granuloma of the jaws: assessment of cell cycle proteins.
        J Oral Pathol Med. 2004; 33: 170-176
        • Suda N.
        • Gillespie M.T.
        • Traianedes K.
        • Zhou H.
        • Ho P.W.
        • Hards D.K.
        • et al.
        Expression of parathyroid hormone-related protein in cells of osteoblast lineage.
        J Cell Physiol. 1996; 166: 94-104
        • Teitelbaum S.L.
        Bone resorption by osteoclasts.
        Science. 2000; 289: 1504-1508
        • Katagiri T.
        • Yamaguchi A.
        • Komaki M.
        • Abe E.
        • Takahashi N.
        • Ikeda T.
        • et al.
        Bone morphogenetic protein–2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage.
        J Cell Biol. 1994; 127: 1755-1766
        • McCauley L.K.
        • Koh A.J.
        • Beecher C.A.
        • Cui Y.
        • Rosol T.J.
        • Franceschi R.T.
        PTH/PTHrP receptor is temporally regulated during osteoblast differentiation and is associated with collagen synthesis.
        J Cell Biochem. 1996; 61: 638-647
        • Moseley J.M.
        • Hayman J.A.
        • Danks J.A.
        • Alcorn D.
        • Grill V.
        • Southby J.
        • et al.
        Immunohistochemical detection of parathyroid hormone–related protein in human fetal epithelia.
        J Clin Endocrinol Metab. 1991; 73: 478-484
        • Tenta R.
        • Sourla A.
        • Lembessis P.
        • Koutsilieris M.
        Bone-related growth factors and zoledronic acid regulate the PTHrP/PTH.1 receptor bioregulation systems in MG-63 human osteosarcoma cells.
        Anticancer Res. 2006; 26: 283-291
        • Liu B.Y.
        • Wu P.W.
        • Bringhurst F.R.
        • Wang J.T.
        Estrogen inhibition of PTH-stimulated osteoclast formation and attachment in vitro: involvement of both PKA and PKC.
        Endocrinology. 2002; 143: 627-635
        • Orestes-Cardoso S.
        • Nefussi J.-R.
        • Lezot F.
        • Oboeuf M.
        • Pereira M.
        • Mesbah M.
        • et al.
        MSX1 is a regulator of bone formation during development and postnatal growth: in vivo investigations in a transgenic mouse model.
        Connect Tissue Res. 2002; 43: 153-160
        • Mackenzie A.
        • Leeming G.L.
        • Jowett A.K.
        • Ferguson M.W.
        • Sharpe P.T.
        The homeobox gene HOX 7.1 has specific regional and temporal expression patterns during early murine craniofacial embryogenesis, especially tooth development in vivo and in vitro.
        Development. 1991; 111: 269-285
        • Song K.
        • Wang Y.
        • Sassoon D.
        Expression of HOX-7.1 in myoblasts inhibits terminal differentiation and induces cell transformation.
        Nature. 1992; 360: 477-481
        • Woloshin P.
        • Song K.
        • Degnin C.
        • Killary A.M.
        • Goldhamer D.J.
        • Sassoon D.
        • et al.
        MSX1 inhibits myoD expression in fibroblast x 10T1/2 cell hybrids.
        Cell. 1995; 82: 611-620
        • Gersch R.P.
        • Lombard F.
        • McGovern S.C.
        • Hadjiargyrou M.
        Reactivation of HOX gene expression during bone regeneration.
        J Orthopaed Res. 2005; 23: 882-890
        • Beck F.
        • Tucci J.
        • Russell A.
        • Senior P.V.
        • Ferguson M.W.
        The expression of the gene coding for parathyroid hormone-related protein (PTHrP) during tooth development in the rat.
        Cell Tissue Res. 1995; 280: 283-290
        • Wise GE Q.B.
        • Huang H.
        • Lumpkin S.J.
        Enhancement of gene expression in rat dental follicle cells by parathyroid hormone-related protein.
        Arch Oral Biol. 2000; 45: 903-909
        • Suda N.
        • Kitahara Y.
        • Hammond V.E.
        • Ohyama K.
        Development of a novel mouse osteoclast culture system including cells of mandibular body and erupting teeth.
        Bone. 2003; 33: 38-45
        • Miah S.M.
        • Hatani T.
        • Qu X.
        • Yamamura H.
        • Sada K.
        Point mutations of 3BP2 identified in human-inherited disease cherubism result in the loss of function.
        Genes Cells. 2004; 9: 993-1004
        • Idowu B.
        • Thomas G.
        • Frow R.
        • Diss T.
        • Flanagan A.
        Mutations in SH3BP2, the cherubism gene, were not detected in central or peripheral giant cell tumours of the jaw.
        Br J Oral Maxillofac Surg. 2008; 46: 229-230
        • de Lange J.
        • van Maarle M.C.
        • van den Akker H.P.
        • Redeker E.J.
        DNA analysis of the SH3BP2 gene in patients with aggressive central giant cell granuloma.
        Br J Oral Maxillofac Surg. 2007; 45: 499-500