Abstract
Pigment epithelium-derived factor (PEDF) is a potent anti-angiogenic factor found in a wide range of fetal and adult tissues, where it is thought to play a role in the regulation of angiogenesis during development. The temporal expression of PEDF during endochondral bone formation has not previously been reported. In this study, we analysed the expression pattern of PEDF in growing mouse hindlimbs from newborn day one through to maturation at week 9, using immunohistochemistry and in situ hybridization. PEDF expression was demonstrated in chondrocytes within the resting, proliferative and upper hypertrophic zones of the epiphyseal growth plate. The pattern of expression was consistent throughout the developmental stages of the mouse. In addition, PEDF was expressed by osteoblasts lining the bone spicules in the ossification zone of metaphyseal bone, as well as by osteoblasts lining cortical periosteum. These novel results demonstrate that PEDF is developmentally expressed in both cartilage and bone cells during endochondral bone formation, and strongly suggest that it may play a regulatory role in the processes of chondrocyte and osteoblast differentiation, endochondral ossification, and bone remodelling during growth and development of long bones.
Similar content being viewed by others
References
J Tombran-Tink GG Chader LV Johnson (1991) ArticleTitlePEDF: a pigment epithelium-derived factor with potent neuronal differentiative activity Exp Eye Res 53 411–414 Occurrence Handle10.1016/0014-4835(91)90248-D Occurrence Handle1:CAS:528:DyaK3MXmsVyktrY%3D Occurrence Handle1936177
FR Steele GJ Chader LV Johnson J Tombran-Tink (1993) ArticleTitlePigment epithelium-derived factor: neurotrophic activity and identification as a member of the serine protease inhibitor gene family Proc Natl Acad Sci USA 90 1526–1530 Occurrence Handle1:CAS:528:DyaK3sXit1Grurc%3D Occurrence Handle8434014
T Araki T Taniwaki SP Becerra GJ Chader JP Schwartz (1998) ArticleTitlePigment epithelium-derived factor (PEDF) differentially protects immature but not mature cerebellar granule cells against apoptotic cell death J Neurosci Res 53 7–15 Occurrence Handle10.1002/(SICI)1097-4547(19980701)53:1<7::AID-JNR2>3.0.CO;2-F Occurrence Handle1:CAS:528:DyaK1cXktFOiurc%3D Occurrence Handle9670988
LJ Houenou AP D’Costa L Li VL Turgeon C Enyadike E Alberdi SP Becerra (1999) ArticleTitlePigment epithelium-derived factor promotes the survival and differentiation of developing spinal motor neurons J Comp Neurol 412 506–514 Occurrence Handle10.1002/(SICI)1096-9861(19990927)412:3<506::AID-CNE9>3.0.CO;2-E Occurrence Handle1:CAS:528:DyaK1MXlvVKmtro%3D Occurrence Handle10441236
RJ Pignolo VJ Cristofalo MO Rotenberg (1993) ArticleTitleSenescent WI-38 cells fail to express EPC-1, a gene induced in young cells upon entry into the G0 state J Biol Chem 268 8949–8957 Occurrence Handle1:CAS:528:DyaK3sXktVWltbk%3D Occurrence Handle8473338
DW Dawson OV Volpert P Gillis SE Crawford H Xu W Benedict NP Bouck (1999) ArticleTitlePigment epithelium-derived factor: a potent inhibitor of angiogenesis Science 285 245–248 Occurrence Handle10.1126/science.285.5425.245 Occurrence Handle1:CAS:528:DyaK1MXks1SjtLo%3D Occurrence Handle10398599
SE Crawford V Stellmach M Ranalli et al. (2001) ArticleTitlePigment epithelium-derived factor (PEDF) in neuroblastoma: a multifunctional mediator of Schwann cell antitumor activity J Cell Sci 114 4421–4428 Occurrence Handle1:CAS:528:DC%2BD38XnvFKlsg%3D%3D Occurrence Handle11792807
JA Doll VM Stellmach NP Bouck et al. (2003) ArticleTitlePigment epithelium-derived factor regulates the vasculature and mass of the prostate and pancreas Nat Med 9 774–780 Occurrence Handle10.1038/nm870 Occurrence Handle1:CAS:528:DC%2BD3sXktFOnurk%3D Occurrence Handle12740569
LP Abramson V Stellmach JA Doll M Cornwell RM Arensman SE Crawford (2003) ArticleTitleWilms’ tumor growth is suppressed by antiangiogenic pigment epithelium-derived factor in a xenograft model J Pediatr Surg 38 336–342 Occurrence Handle10.1053/jpsu.2003.50104 Occurrence Handle12632345
C Meyer L Notari SP Becerra (2002) ArticleTitleMapping the type I collagen-binding site on pigment epithelium-derived factor Implications for its antiangiogenic activity. J Biol Chem 277 45400–45407 Occurrence Handle1:CAS:528:DC%2BD38Xosl2lur8%3D
J Tombran-Tink K Mazuruk IR Rodriguez D Chung T Linker E Englander GJ Chader (1996) ArticleTitleOrganization, evolutionary conservation, expression and unusual Alu density of the human gene for pigment epithelium-derived factor, a unique neurotrophic serpin Mol Vis 2 1–11
YQ Wu SP Becerra (1996) ArticleTitleProteolytic activity directed toward pigment epithelium-derived factor in vitreous of bovine eyes Implications of proteolytic processing. Invest Ophthalmol Vis Sci 37 1984–1993 Occurrence Handle1:STN:280:BymH3cbhsFE%3D
G Gao Y Li D Zhang S Gee C Crosson J Ma (2001) ArticleTitleUnbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization FEES Lett 489 270–276 Occurrence Handle10.1016/S0014-5793(01)02110-X Occurrence Handle1:CAS:528:DC%2BD3MXpsF2lsA%3D%3D
N Ogata M Nishikawa T Nishimura Y Mitsuma M Matsumura (2002) ArticleTitleInverse levels of pigment epithelium-derived factor and vascular endothelial growth factor in the vitreous of eyes with rhegmatogenous retinal detachment and proliferative vitreoretinopathy Am J Ophthalmol 133 851–852 Occurrence Handle10.1016/S0002-9394(02)01406-X Occurrence Handle1:CAS:528:DC%2BD38XktVCit78%3D Occurrence Handle12036691
A Horner NJ Bishop S Bord C Beeton AW Kelsall N Coleman JE Compston (1999) ArticleTitleImmunolocalisation of vascular endothelial growth factor (VEGF) in human neonatal growth plate cartilage J Anat 194 519–524 Occurrence Handle10.1046/j.1469-7580.1999.19440519.x Occurrence Handle1:CAS:528:DyaK1MXlt1Sgtbc%3D Occurrence Handle10445820
S Jingushi SP Scully ME Joyce Y Sugioka ME Bolander (1995) ArticleTitleTransforming growth factor-beta 1 and fibroblast growth factors in rat growth plate J Orthop Res 13 761–768 Occurrence Handle10.1002/jor.1100130516 Occurrence Handle1:CAS:528:DyaK28Xktl2gsw%3D%3D Occurrence Handle7472755
MF Carlevaro A Albini D Ribatti et al. (1997) ArticleTitleTransferrin promotes endothelial cell migration and invasion: implication in cartilage neovascularization J Cell Biol 136 1375–1384 Occurrence Handle10.1083/jcb.136.6.1375 Occurrence Handle1:CAS:528:DyaK2sXitFenur8%3D Occurrence Handle9087450
C Shukunami K Iyama H Inoue Y Hiraki (1999) ArticleTitleSpatiotemporal pattern of the mouse chondromodulin-I gene expression and its regulatory role in vascular invasion into cartilage during endochondral bone formation Int J Dev Biol 43 39–49 Occurrence Handle1:CAS:528:DyaK1MXitFCitLY%3D Occurrence Handle10213081
WH Cheung KM Lee KP Fung KS Leung (2001) ArticleTitleGrowth plate chondrocytes inhibit neo-angiogenesis — a possible mechanism for tumor control Cancer Lett 163 25–32 Occurrence Handle10.1016/S0304-3835(00)00653-4 Occurrence Handle1:CAS:528:DC%2BD3MXksVWrtg%3D%3D Occurrence Handle11163105
GMY Quan J Ojaimi APW Nadesapillai H Zhou PFM Choong (2002) ArticleTitleResistance of epiphyseal cartilage to invasion by osteosarcoma is likely to be due to the expression of anti-angiogenic factors Pathobiology 70 361–367 Occurrence Handle10.1159/000071277 Occurrence Handle12865633
JL Fisher CL Field H Zhou TL Harris MA Henderson PFM Choong (2000) ArticleTitleUrokinase plasminogen activator system gene expression is increased in human breast carcinoma and its bone metastases—a comparison of normal breast tissue, non-invasive and invasive carcinoma and osseous metastases Breast Cancer Res Treat 61 1–12 Occurrence Handle10.1023/A:1006445129195 Occurrence Handle1:CAS:528:DC%2BD3cXlslaqs7Y%3D Occurrence Handle10930085
Y Hiraki H Inoue K Iyama et al. (1997) ArticleTitleIdentification of chondromodulin I as a novel endothelial cell growth inhibitor Purification and its localization in the avascular zone of epiphyseal cartilage, J Biol Chem 272 32419–32426
MA Moses D Wiederschain I Wu et al. (1999) ArticleTitleTroponin I is present in human cartilage and inhibits angiogenesis Proc Natl Acad Sci USA 96 2645–2650 Occurrence Handle10.1073/pnas.96.6.2645 Occurrence Handle1:CAS:528:DyaK1MXhvFyltb8%3D Occurrence Handle10077564
N Liu RK Lapcevich CB Underhill et al. (2001) ArticleTitleMetastatin: a hyaluronan-binding complex from cartilage that inhibits tumor growth Cancer Res 61 1022–1028 Occurrence Handle1:CAS:528:DC%2BD3MXhsFSru7Y%3D Occurrence Handle11221828
WH Cheung KM Lee KP Fung PY Lui KS Leung (2001) ArticleTitleTGF-beta 1 is the factor secreted by proliferative chondrocytes to inhibit neo-angiogenesis J Cell Biochem (suppl) 36 79–88
M Garcia-Ramirez N Toran P Andaluz A Carrascosa L Audi (2000) ArticleTitleVascular endothelial growth factor is expressed in human fetal growth cartilage J Bone Miner Res 15 534–540 Occurrence Handle1:CAS:528:DC%2BD3cXitFakt74%3D Occurrence Handle10750568
MF Carlevaro S Cermelli R Cancedda F Descalzi Cancedda (2000) ArticleTitleVascular endothelial growth factor (VEGF) in cartilage neovascularization and chondrocyte differentiation: auto-paracrine role during endochondral bone formation J Cell Sci 113 59–69 Occurrence Handle1:CAS:528:DC%2BD3cXhtVaksr8%3D Occurrence Handle10591625
M Alini A Marriott T Chen S Abe AR Poole (1996) ArticleTitleA novel angiogenic molecule produced at the time of chondrocyte hypertrophy during endochondral bone formation Dev Biol 176 124–132 Occurrence Handle10.1006/dbio.1996.9989 Occurrence Handle1:CAS:528:DyaK28Xjt1GksL0%3D Occurrence Handle8654888
HP Gerber (1999) ArticleTitleVascular endothelial growth factor plays an important part in longitudinal bone growth by stimulating angiognesis into the growth plate Nat Med 5 623–628 Occurrence Handle10.1038/9467 Occurrence Handle1:CAS:528:DyaK1MXjs1Kmtrc%3D Occurrence Handle10371499
M Yin C Gentili E Koyama M Zasloff M Pacifici (2002) ArticleTitleAntiangiogenic treatment delays chondrocyte maturation and bone formation during limb skeletogenesis J Bone Miner Res 17 56–65 Occurrence Handle1:CAS:528:DC%2BD38XktFyitw%3D%3D Occurrence Handle11771670
H Shao I Schvartz S Shaltiel (2003) ArticleTitleSecretion of pigment epithelium-derived factor Eur J Biochem 270 822–831 Occurrence Handle10.1046/j.1432-1033.2003.03374.x Occurrence Handle1:CAS:528:DC%2BD3sXitlCmt7o%3D Occurrence Handle12603315
SV Petersen Z Valnickova JJ Enghild (2003) ArticleTitleA physiologically relevant concentration of pigment epithelium-derived factor (PEDF) in human blood Purification and characterization. Biochem J 374 199–206 Occurrence Handle1:CAS:528:DC%2BD3sXmtF2gsrk%3D
M Simonovic PG Gettins K Volz (2001) ArticleTitleCrystal structure of human PEDF, a potent anti-angiogenic and neurite growth-promoting factor Proc Natl Acad Sci USA 98 11131–11135 Occurrence Handle10.1073/pnas.211268598 Occurrence Handle1:CAS:528:DC%2BD3MXnt1yqsbs%3D Occurrence Handle11562499
N Yasui T Mori D Morito O Matsushita H Kourai K Nagata T Koide (2003) ArticleTitleDual-site recognition of different extracellular matrix components by anti-angiogenic/neurotrophic serpin, PEDF Biochemistry 42 3160–3167 Occurrence Handle10.1021/bi0206558 Occurrence Handle1:CAS:528:DC%2BD3sXhslSmtbo%3D Occurrence Handle12641447
K Kozaki O Miyaishi O Koiwai et al. (1998) ArticleTitleIsolation, purification, and characterization of a collagen-associated serpin, caspin, produced by murine colon adenocarcinoma cells J Biol Chem 273 15125–15130 Occurrence Handle10.1074/jbc.273.24.15125 Occurrence Handle1:CAS:528:DyaK1cXktVelsrk%3D Occurrence Handle9614124
J Tombran-Tink CJ Barnstable (2004) ArticleTitleOsteoblasts and osteoclasts express PEDF, VEGF-A isoforms and VEGF receptors: possible mediators of angiogenesis and matrix remodeling in the bone Biochem Biophys Res Commun 316 573–579 Occurrence Handle10.1016/j.bbrc.2004.02.076 Occurrence Handle1:CAS:528:DC%2BD2cXitFKgsr4%3D Occurrence Handle15020256
V Stellmach SE Crawford W Zhou N Bouck (2001) ArticleTitlePrevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor Proc Natl Acad Sci USA 98 2593–2597 Occurrence Handle10.1073/pnas.031252398 Occurrence Handle1:CAS:528:DC%2BD3MXhslKmsLg%3D Occurrence Handle11226284
OV Volpert T Zaichuk W Zhou F Reiher TA Ferguson PM Stuart M Amin NP Bouck (2002) ArticleTitleInducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor Nat Med 8 349–357 Occurrence Handle10.1038/nm0402-349 Occurrence Handle1:CAS:528:DC%2BD38XivVGmsLY%3D Occurrence Handle11927940
T Aizawa HI Roach S Kokubun Y Tanaka (1998) ArticleTitleChanges in the expression of fas, osteonectin and osteocalcin with age in the rabbit growth plate J Bone Joint Surg Br 80 880–887 Occurrence Handle10.1302/0301-620X.80B5.8430 Occurrence Handle1:STN:280:DyaK1cvjvFyguw%3D%3D Occurrence Handle9768903
S Hashimoto M Setareh RL Ochs M Lotz (1997) ArticleTitleFas/Fas ligand expression and induction of apoptosis in chondrocytes Arthritis Rheum 40 1749–1755 Occurrence Handle1:CAS:528:DyaK2sXntFWqsbc%3D Occurrence Handle9336406
J Tombran-Tink H Pawar A Swaroop I Rodriguez GJ Chader (1994) ArticleTitleLocalization of the gene for pigment epithelium-derived factor (PEDF) to chromosome 17p13.1 and expression in cultured human retinoblastoma cells Genomics 19 266–272 Occurrence Handle10.1006/geno.1994.1057 Occurrence Handle1:CAS:528:DyaK2cXlt1Kgurs%3D Occurrence Handle8188257
GM Seigel J Tombran-Tink SP Becerra GJ Chader DA Diloreto Particledel SuffixJr. C Cerro ES Lazar Particledel M Cerro (1994) ArticleTitleDifferentiation of Y79 retinoblastoma cells with pigment epithelial- derived factor and interphotoreceptor matrix wash: effects on tumorigenicity Growth Factors 10 289–297 Occurrence Handle1:STN:280:ByqC3c7isFY%3D Occurrence Handle7803045
Acknowledgments
This study was supported by the Victorian Orthopaedic Research Trust, Australian Orthopaedic Association, and the Anti-Cancer Council of Victoria. The first author is a recipient of scholarships awarded by the Faculty of Medicine, University of Melbourne, and the National Health and Medical Research Council of Australia. The authors would like to thank Professor T. J. Martin for his helpful advice regarding the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Quan, G.M.Y., Ojaimi, J., Li, Y. et al. Localization of Pigment Epithelium-Derived Factor in Growing Mouse Bone. Calcif Tissue Int 76, 146–153 (2005). https://doi.org/10.1007/s00223-004-0068-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00223-004-0068-2