Skip to main content

Advertisement

SpringerLink
Log in

Genes influencing spinal bone mineral density in inbred F344, LEW, COP, and DA rats

  • Original Paper
  • Published:
Functional & Integrative Genomics Aims and scope Submit manuscript

Abstract

Previously, we identified the regions of chromosomes 10q12–q31 and 15p16–q21 harbor quantitative trait loci (QTLs) for lumbar volumetric bone mineral density (vBMD) in female F2 rats derived from Fischer 344 (F344) × Lewis (LEW) and Copenhagen 2331 (COP) × Dark Agouti (DA) crosses. The purpose of this study is to identify the candidate genes within these QTL regions contributing to the variation in lumbar vBMD. RNA was extracted from bone tissue of F344, LEW, COP, and DA rats. Microarray analysis was performed using Affymetrix Rat Genome 230 2.0 Arrays. Genes differentially expressed among the rat strains were then ranked based on the strength of the correlation with lumbar vBMD in F2 animals derived from these rats. Quantitative PCR (qPCR) analysis was performed to confirm the prioritized candidate genes. A total of 285 genes were differentially expressed among all strains of rats with a false discovery rate less than 10%. Among these genes, 18 candidate genes were prioritized based on their strong correlation (r 2 > 0.90) with lumbar vBMD. Of these, 14 genes (Akap1, Asgr2, Esd, Fam101b, Irf1, Lcp1, Ltc4s, Mdp-1, Pdhb, Plxdc1, Rabep1, Rhot1, Slc2a4, Xpo4) were confirmed by qPCR. We identified several novel candidate genes influencing spinal vBMD in rats.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Aitman TJ, Glazier AM, Wallace CA, Cooper LD, Norsworthy PJ, Wahid FN, Al-Majali KM, Trembling PM, Mann CJ, Shoulders CC, Graf D, St Lezin E, Kurtz TW, Kren V, Pravenec M, Ibrahimi A, Abumrad NA, Stanton LW, Scott J (1999) Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nature Genet 21:76–83

    Article  PubMed  CAS  Google Scholar 

  • Alam I, Sun Q, Liu L, Koller DL, Liu L, Edenberg HJ, Econs MJ, Foroud T, Turner CH (2008) Genomic expression analysis of rat chromosome 4 for skeletal traits at femoral neck. Physiol Genomics 35:191–196

    Article  PubMed  CAS  Google Scholar 

  • Arden NK, Baker J, Hogg C, Bann K, Spector TD (1996) The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: a study of postmenopausal twins. J Bone Miner Res 11:530–534

    Article  PubMed  CAS  Google Scholar 

  • Beamer WG, Shultz KL, Donahue LR, Churchill GA, Sen S, Wergedal JR, Baylink DJ, Rosen CJ (2001) Quantitative trait loci for femoral and lumbar vertebral bone mineral density in C57BL/6J and C3H/HeJ inbred strains of mice. J Bone Miner Res 16:1195–1206

    Article  PubMed  CAS  Google Scholar 

  • Benes H, Weinstein RS, Zheng W, Thaden JJ, Jilka RL, Manolagas SC, Shmookler Reis RJ (2000) Chromosomal mapping of osteopenia-associated quantitative trait loci using closely related mouse strains. J Bone Miner Res 15:626–633

    Article  PubMed  CAS  Google Scholar 

  • Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc (B) 57:289–290

    Google Scholar 

  • Calvano SE, Xiao W, Richards DR, Felciano RM, Baker HV, Cho RJ, Chen RO, Brownstein BH, Cobb JP, Tschoeke SK, Miller-Graziano C, Moldawer LL, Mindrinos MN, Davis RW, Tompkins RG, Lowry SF (2005) A network-based analysis of systemic inflammation in humans. Nature 437:1032–1037

    Article  PubMed  CAS  Google Scholar 

  • Chen HB, Shen J, Ip YT, Xu L (2006) Identification of phosphatases for Smad in the BMP/DPP pathway. Genes Dev 20:648–653

    Article  PubMed  CAS  Google Scholar 

  • Cooper C, Atkinson EJ, Jacobsen SJ, O'Fallon WM, Melton LJ 3rd (1993) Population-based study of survival after osteoporotic fractures. Am J Epidemiol 137:1001–1005

    PubMed  CAS  Google Scholar 

  • Deng HW, Xu FH, Huang QY, Shen H, Deng H, Conway T, Liu YJ, Liu YZ, Li JL, Zhang HT, Davies KM, Recker RR (2002) A whole-genome linkage scan suggests several genomic regions potentially containing quantitative trait loci for osteoporosis. J Clin Endocrinol Metab 87:5151–5159

    Article  PubMed  CAS  Google Scholar 

  • Devoto M, Shimoya K, Caminis J, Ott J, Tnenhouse A, Whyte MP, Sereda L, Hall S, Considine E, Williams CJ (1998) First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q. Euro J Human Genet 6:151–157

    Article  CAS  Google Scholar 

  • Duncan EL, Browon MA, Sinsheimer J, Bell J, Carr AJ, Wordsworth BP, Wass JA (1999) Suggestive linkage of the parathyroid receptor type 1 to osteoporosis. J Bone Miner Res 14:1993–1999

    Article  PubMed  CAS  Google Scholar 

  • Farber CR, van Nas A, Ghazalpour A, Aten JE, Doss S, Sos B, Schadt EE, Ingram-Drake L, Davis RC, Horvath S, Smith DJ, Drake TA, Lusis AJ (2009) An integrative genetics approach to identify candidate genes regulating BMD: combining linkage, gene expression, and association. J Bone Miner Res 24:105–116

    Article  PubMed  CAS  Google Scholar 

  • Fuchs B, Mahlum E, Halder C, Maran A, Yaszemski M, Bode B, Bolander M, Sarkar G (2007) High expression of tumor endothelial marker 7 is associated with metastasis and poor survival of patients with osteogenic sarcoma. Gene 399:137–143

    Article  PubMed  CAS  Google Scholar 

  • Garnero P, Arden NK, Griffiths G, Delmas PD, Spector TD (1996) Genetic influence on bone turnover in postmenopausal twins. J Clin Endocrinol Metab 81:140–146

    Article  PubMed  CAS  Google Scholar 

  • Giustina A, Mazziotti G, Canalis E (2008) Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev 29:535–559

    Article  PubMed  CAS  Google Scholar 

  • Hsu YH, Xu X, Terwedow HA, Niu T, Hong X, Wu D, Wang L, Brain JD, Bouxsein ML, Cummings SR, Rosen CJ, Xu X (2007) Large-scale genome-wide linkage analysis for loci linked to BMD at different skeletal sites in extreme selected sibships. J Bone Miner Res 22:184–194

    Article  PubMed  CAS  Google Scholar 

  • Huang C, Ross PD, Wasnich RD (1996) Vertebral fracture and other predictors of physical impairment and health care utilization. Arch Intern Med 156:2469–2475

    Article  PubMed  CAS  Google Scholar 

  • Ioannidis JP, Ng MY, Sham PC, Zintzaras E, Lewis CM, Deng HW, Econs MJ, Karasik D, Devoto M, Kammerer CM, Spector T, Andrew T, Cupples LA, Duncan EL, Foroud T, Kiel DP, Koller D, Langdahl B, Mitchell BD, Peacock M, Recker R, Shen H, Sol-Church K, Spotila LD, Uitterlinden AG, Wilson SG, Kung AW, Ralston SH (2007) Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. J Bone Miner Res 22:173–183

    Article  PubMed  CAS  Google Scholar 

  • Johnson ML, Gong G, Kimberling W, Reckér SM, Kimmel DB, Recker RB (1997) Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13). Am J Hum Genet 60:1326–1332

    Article  PubMed  CAS  Google Scholar 

  • Kado DM, Browner WS, Palermo L, Nevitt MC, Genant HK, Cummings SR (1999) Vertebral fractures and mortality in older women: a prospective study. Study of osteoporotic fractures research group. Arch Intern Med 159:1215–1220

    Article  PubMed  CAS  Google Scholar 

  • Kanis JA, Melton LJ, Christiansen C, Johnston CC, Khaltaev N (1994) The diagnosis of osteoporosis. J Bone Miner Res 9:1137–1141

    Article  PubMed  CAS  Google Scholar 

  • Karasik D, Myers RH, Cupples LA, Hannan MT, Gagnon DR, Herbert A, Kiel DP (2002) Genome screen for quantitative trait loci contributing to normal variation in bone mineral density: the Framingham Study. J Bone Miner Res 17:1718–1727

    Article  PubMed  CAS  Google Scholar 

  • Karp CL, Grupe A, Schadt E, Ewart SL, Keane-Moore M, Cuomo PJ, Köhl J, Wahl L, Kuperman D, Germer S, Aud D, Peltz G, Wills-Karp M (2000) Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nat Immunol 1:221–226

    Article  PubMed  CAS  Google Scholar 

  • Kaufman JM, Ostertag A, Saint-Pierre A, Cohen-Solal M, Boland A, Van Pottelbergh I, Toye K, de Vernejoul MC, Martinez M (2008) Genome-wide linkage screen of bone mineral density (BMD) in European pedigrees ascertained through a male relative with low BMD values: evidence for quantitative trait loci on 17q21–23, 11q12–13, 13q12–14, and 22q11. J Clin Endocrinol Metab 93:3755–3762

    Article  PubMed  CAS  Google Scholar 

  • Koller DL, Econs MJ, Morin PA, Christian JC, Hui SL, Parry P, Curran ME, Rodriguez LA, Conneally PM, Joslyn G, Peacock M, Johnston CC, Foroud T (2000) Genome screen for QTLs contributing to normal variation in bone mineral density and osteoporosis. J Clin Endocrinol Metab 85:3116–3120

    Article  PubMed  CAS  Google Scholar 

  • Koller DL, Alam I, Sun Q, Liu L, Fishburn T, Carr LG, Econs MJ, Foroud T, Turner CH (2005) Genome screen for bone mineral density phenotypes in Fischer 344 and Lewis rats. Mammalian Genome 16:578–586

    Article  PubMed  Google Scholar 

  • Koller DL, Liu L, Alam I, Sun Q, Econs MJ, Foroud T, Turner CH (2008) Linkage screen for BMD phenotypes in male and female COP and DA rat strains. J Bone Miner Res 23:1382–1388

    Article  PubMed  Google Scholar 

  • Koseki T, Gao Y, Okahashi N, Murase Y, Tsujisawa T, Sato T, Yamato K, Nishihara T (2002) Role of TGF-beta family in osteoclastogenesis induced by RANKL. Cell Signal 14:31–36

    Article  PubMed  CAS  Google Scholar 

  • Leidig-Bruckner G, Minne HW, Schlaich C, Wagner G, Scheidt-Nave C, Bruckner T, Gebest HJ, Ziegler R (1997) Clinical grading of spinal osteoporosis: quality of life components and spinal deformity in women with chronic low back pain and women with vertebral osteoporosis. J Bone Miner Res 12:663–675

    Article  PubMed  CAS  Google Scholar 

  • Le Stunff C, Rotwein P (1998) Growth hormone stimulates interferon regulatory factor-1 gene expression in the liver. Endocrinology 139:859–866

    Article  PubMed  Google Scholar 

  • Li X, Liu H, Qin L, Tamasi J, Bergenstock M, Shapses S, Feyen JH, Notterman DA, Partridge NC (2007) Determination of dual effects of parathyroid hormone on skeletal gene expression in vivo by microarray and network analysis. J Biol Chem 282:33086–33097

    Article  PubMed  CAS  Google Scholar 

  • Lips P, Cooper C, Agnusdei D, Caulin F, Egger P, Johnell O, Kanis JA, Kellingray S, Leplege A, Liberman UA, McCloskey E, Minne H, Reeve J, Reginster JY, Scholz M, Todd C, de Vernejoul MC, Wiklund I (1999) Quality of life in patients with vertebral fractures: validation of the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO). Working Party for Quality of Life of the European Foundation for Osteoporosis. Osteoporos Int 10:150–160

    Article  PubMed  CAS  Google Scholar 

  • Lomaga MA, Yeh WC, Sarosi I, Duncan GS, Furlonger C, Ho A, Morony S, Capparelli C, Van G, Kaufman S, van der Heiden A, Itie A, Wakeham A, Khoo W, Sasaki T, Cao Z, Penninger JM, Paige CJ, Lacey DL, Dunstan CR, Boyle WJ, Goeddel DV, Mak TW (1999) TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 13:1015–1024

    Article  PubMed  CAS  Google Scholar 

  • Lynch MP, Capparelli C, Stein JL, Stein GS, Lian JB (1998) Apoptosis during bone-like tissue development in vitro. J Cell Biochem 68:31–49

    Article  PubMed  CAS  Google Scholar 

  • Macdonald KK, Cheung CY, Anseth KS (2007) Cellular delivery of TGFbeta1 promotes osteoinductive signalling for bone regeneration. J Tissue Eng Regen Med 1:314–317

    Article  PubMed  CAS  Google Scholar 

  • Magnusson MK, Meade KE, Brown KE, Arthur DC, Krueger LA, Barrett AJ, Dunbar CE (2001) Rabaptin-5 is a novel fusion partner to platelet-derived growth factor beta receptor in chronic myelomonocytic leukemia. Blood 98:2518–2525

    Article  PubMed  CAS  Google Scholar 

  • Maor G, Karnieli E (1999) The insulin-sensitive glucose transporter (GLUT4) is involved in early bone growth in control and diabetic mice, but is regulated through the insulin-like growth factor I receptor. Endocrinology 140:1841–1851

    Article  PubMed  CAS  Google Scholar 

  • McClintick JN, Edenberg HJ (2006) Effects of filtering by present call on analysis of microarray experiments. BMC Bioinformatics 7:49

    Article  PubMed  CAS  Google Scholar 

  • Mengus G, Fadloun A, Kobi D, Thibault C, Perletti L, Michel I, Davidson I (2005) TAF4 inactivation in embryonic fibroblasts activates TGFbeta signalling and autocrine growth. EMBO J 24:2753–2767

    Article  PubMed  CAS  Google Scholar 

  • Nakamura I, Jimi E (2006) Regulation of osteoclast differentiation and function by interleukin-1. Vitam Horm 74:357–3570

    Article  PubMed  CAS  Google Scholar 

  • Olney RC (2003) Regulation of bone mass by growth hormone. Med Pediatr Oncol 41:228–234

    Article  PubMed  Google Scholar 

  • Peacock M, Turner CH, Econs MJ, Foroud T (2002) Genetics of osteoporosis. Endocr Rev 23:378–383

    Article  Google Scholar 

  • Polzer K, Joosten L, Gasser J, Distler JH, Ruiz G, Baum W, Redlich K, Bobacz K, Smolen JS, van den Berg W, Schett G, Zwerina J (2009) IL-1 is essential for systemic inflammatory bone loss. Ann Rheum Dis (in press). PMID: 19196726

  • Ralston SH (2005) Genetic determinants of osteoporosis. Curr Opin Rheumatol 17:475–479

    Article  PubMed  Google Scholar 

  • Ray NF, Chan JK, Thamer M, Melton LJ (1997) Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res 12:24–35

    Article  PubMed  CAS  Google Scholar 

  • Riddick CA, Serio KJ, Hodulik CR, Ring WL, Regan MS, Bigby TD (1999) TGF-beta increases leukotriene C4 synthase expression in the monocyte-like cell line, THP-1. J Immunol 162:1101–1107

    PubMed  CAS  Google Scholar 

  • Rozzo SJ, Allard JD, Choubey D, Vyse TJ, Izui S, Peltz G, Kotzin BL (2001) Evidence for an interferon-inducible gene, Ifi202, in the susceptibility to systemic lupus. Immunity 15:435–443

    Article  PubMed  CAS  Google Scholar 

  • Schneider HG, Michelangeli VP, Frampton RJ, Grogan JL, Ikeda K, Martin TJ, Findlay DM (1992) Transforming growth factor-beta modulates receptor binding of calciotropic hormones and G protein-mediated adenylate cyclase responses in osteoblast-like cells. Endocrinology 131:1383–1389

    Article  PubMed  CAS  Google Scholar 

  • Shen H, Zhang YY, Long JR, Xu FH, Liu YZ, Xiao P, Zhao LJ, Xiong DH, Liu YJ, Dvornyk V, Rocha-Sanchez S, Liu PY, Li JL, Conway T, Davies KM, Recker RR, Deng HW (2004) A genome-wide linkage scan for bone mineral density in an extended sample: evidence for linkage on 11q23 and Xq27. J Med Genet 41:743–751

    Article  PubMed  CAS  Google Scholar 

  • Smyth GK (2004) Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3:1–26

    Google Scholar 

  • Sozzi G, Miozzo M, Di Palma S, Minelli A, Calderone C, Danesino C, Pastorino U, Pierotti MA, Della Porta G (1990) Involvement of the region 13q14 in a patient with adamantinoma of the long bones. Hum Genet 85:513–515

    Article  PubMed  CAS  Google Scholar 

  • Stone KL, Seeley DG, Lui LY, Cauley JA, Ensrud K, Browner WS, Nevitt MC, Cummings SR (2003) BMD at multiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures. J Bone Miner Res 18:1947–1954

    Article  PubMed  Google Scholar 

  • Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS, Bagger Y, Christiansen C, Reynisdottir I, Grant SF, Jonasson K, Frigge ML, Gulcher JR, Sigurdsson G, Stefansson K (2003) Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS Biol 1:E69

    Article  PubMed  Google Scholar 

  • Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Center JR, Nguyen TV, Bagger Y, Gulcher JR, Eisman JA, Christiansen C, Sigurdsson G, Kong A, Thorsteinsdottir U, Stefansson K (2008) Multiple genetic loci for bone mineral density and fractures. N Engl J Med 358:2355–2365

    Article  PubMed  CAS  Google Scholar 

  • Swanton E, Bishop N, Woodman P (1999) Human rabaptin-5 is selectively cleaved by caspase-3 during apoptosis. J Biol Chem 274:37583–37590

    Article  PubMed  CAS  Google Scholar 

  • Tsai JA, Rong H, Torring O, Matsushita H, Bucht E (2000) Interleukin-1beta upregulates PTHrP-mRNA expression and protein production and decreases TGF-beta in normal human osteoblast-like cells. Calcif Tissue Int 66:363–369

    Article  PubMed  Google Scholar 

  • Turner CH, Roeder RK, Wieczorek A, Foroud T, Liu G, Peacock M (2001) Variability in skeletal mass, structure, and biomechanical properties among inbred strains of rats. J Bone Miner Res 16:1532–1539

    Article  PubMed  CAS  Google Scholar 

  • Wada Y, Sato M, Niimi M, Tamaki M, Ishida T, Takahara J (1995) Inhibitory effects of interleukin-1 on growth hormone secretion in conscious male rats. Endocrinology 136:3936–3941

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Zhou J, Bondy CA (1999) Igf1 promotes longitudinal bone growth by insulin-like actions augmenting chondrocyte hypertrophy. FASEB J 13:1985–1990

    PubMed  CAS  Google Scholar 

  • Wilson SG, Reed PW, Bansal A, Chiano M, Lindersson M, Langdown M, Prince RL, Thompson D, Thompson E, Bailey M, Kleyn PW, Sambrook P, Shi MM, Spector TD (2003) Comparison of genome screens for two independent cohorts provides replication of suggestive linkage of bone mineral density to 3p21 and 1p36. Am J Hum Genet 72:144–155

    Article  PubMed  CAS  Google Scholar 

  • Zhou H, Choong PC, Chou ST, Kartsogiannis V, Martin TJ, Ng KW (1995) Transforming growth factor beta 1 stimulates bone formation and resorption in an in-vivo model in rabbits. Bone 17:443S–448S

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the US National Institutes of Health through the following grants: RO1AR047822, P01AG018397, and AA10707. Microarray analysis was carried out in the Center for Medical Genomics at Indiana University School of Medicine, which is supported in part by the Indiana Genomics Initiative (INGEN®, supported in part by The Lilly Endowment Inc.).

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, 1120 South Drive, Fesler Hall 115, Indianapolis, IN, 46202-5251, USA

    Imranul Alam, Qiwei Sun & Charles H. Turner

  2. Medical and Molecular Genetics, Indiana University Purdue University Indianapolis (IUPUI), Indianapolis, IN, USA

    Daniel L. Koller, Lixiang Liu & Tatiana Foroud

  3. Medicine, Indiana University Purdue University Indianapolis (IUPUI), Indianapolis, IN, USA

    Yunlong Liu

  4. Biochemistry and Molecular Biology, Indiana University Purdue University Indianapolis (IUPUI), Indianapolis, IN, USA

    Howard J. Edenberg

Authors
  1. Imranul Alam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qiwei Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel L. Koller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lixiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yunlong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Howard J. Edenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tatiana Foroud
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Charles H. Turner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charles H. Turner.

Additional information

Funding Source: US National Institutes of Health.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alam, I., Sun, Q., Koller, D.L. et al. Genes influencing spinal bone mineral density in inbred F344, LEW, COP, and DA rats. Funct Integr Genomics 10, 63–72 (2010). https://doi.org/10.1007/s10142-009-0147-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10142-009-0147-6

Keywords

Search

Navigation