Skip to main content
Log in

Type I diabetic bone phenotype is location but not gender dependent

  • Original Paper
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

Bone is highly dynamic and responsive. Bone location, bone type and gender can influence bone responses (positive, negative or none) and magnitude. Type I diabetes induces bone loss and increased marrow adiposity in the tibia. We tested if this response exhibits gender and location dependency by examining femur, vertebrae and calvaria of male and female, control and diabetic BALB/c mice. Non-diabetic male mice exhibited larger body, muscle, and fat mass, and increased femur BMD compared to female mice, while vertebrae and calvarial bone parameters did not exhibit gender differences. Streptozotocin-induced diabetes caused a reduction in BMD at all sites examined irrespective of gender. Increased marrow adiposity was evident in diabetic femurs and calvaria (endochondrial and intramembranous formed bones, respectively), but not in vertebrae. Leptin-deficient mice also exhibit location dependent bone responses and we found that serum leptin levels were significantly lower in diabetic compared to control mice. However, in contrast to leptin-deficient mice, the vertebrae of T1-diabetic mice exhibit bone loss, not gain. Taken together, our findings indicate that TI-diabetic bone loss in mice is not gender, bone location or bone type dependent, while increased marrow adiposity is location dependent.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Ahdjoudj S, Lasmoles F, Holy X, Zerath E, Marie PJ (2002) Transforming growth factor beta2 inhibits adipocyte differentiation induced by skeletal unloading in rat bone marrow stroma. J Bone Miner Res 17:668–677

    Article  PubMed  CAS  Google Scholar 

  • Aronow MA, Gerstenfeld LC, Owen TA, Tassinari MS, Stein GS, Lian JB (1990) Factors that promote progressive development of the osteoblast phenotype in cultured fetal rat calvaria cells. J Cell Physiol 143:213–221

    Article  PubMed  CAS  Google Scholar 

  • Auwerx J, Dequeker J, Bouillon R, Geusens P, Nijs J (1988) Mineral metabolism and bone mass at peripheral and axial skeleton in diabetes mellitus. Diabetes 37:8–12

    Article  PubMed  CAS  Google Scholar 

  • Bogdanovic Z, Huang YF, Dodig M, Clark SH, Lichtler AC, Kream BE (2000) Parathyroid hormone inhibits collagen synthesis and the activity of rat col1a1 transgenes mainly by a cAMP-mediated pathway in mouse calvariae. J Cell Biochem 77:149–158

    Article  PubMed  CAS  Google Scholar 

  • Botolin S, McCabe LR (2006) Inhibition of PPARgamma prevents type I diabetic bone marrow adiposity but not bone loss. J Cell Physiol 209(3):967–976

    Article  PubMed  CAS  Google Scholar 

  • Botolin S, McCabe LR (2007) Bone loss and increased bone adiposity in spontaneous and pharmacologically induced diabetic mice. Endocrinology 148:198–205

    Article  PubMed  CAS  Google Scholar 

  • Botolin S, Faugere MC, Malluche H, Orth M, Meyer R, McCabe LR (2005) Increased bone adiposity and peroxisomal proliferator-activated receptor-gamma2 expression in type I diabetic mice. Endocrinology 146:3622–3631

    Article  PubMed  CAS  Google Scholar 

  • Bouillon R, Bex M, Van Herck E, Laureys J, Dooms L, Lesaffre E, Ravussin E (1995) Influence of age, sex, and insulin on osteoblast function: osteoblast dysfunction in diabetes mellitus. J Clin Endocrinol Metab 80:1194–1202

    Article  PubMed  CAS  Google Scholar 

  • Buysschaert M, Cauwe F, Jamart J, Brichant C, De Coster P, Magnan A, Donckier J (1992) Proximal femur density in type 1 and 2 diabetic patients. Diabete Metab 18:32–37

    PubMed  CAS  Google Scholar 

  • Carle F, Gesuita R, Bruno G, Coppa GV, Falorni A, Lorini R, Martinucci ME, Pozzilli P, Prisco F, Songini M, Tenconi MT, Cherubini V (2004) Diabetes incidence in 0- to 14-year age-group in Italy: a 10-year prospective study. Diabetes Care 27:2790–2796

    Article  PubMed  Google Scholar 

  • Casu A, Pascutto C, Bernardinelli L, Songini M (2004) Type 1 diabetes among sardinian children is increasing: the Sardinian diabetes register for children aged 0–14 years (1989–1999). Diabetes Care 27:1623–1629

    Article  PubMed  Google Scholar 

  • Chan GK, Miao D, Deckelbaum R, Bolivar I, Karaplis A, Goltzman D (2003) Parathyroid hormone-related peptide interacts with bone morphogenetic protein 2 to increase osteoblastogenesis and decrease adipogenesis in pluripotent C3H10T 1/2 mesenchymal cells. Endocrinology 144:5511–5520

    Article  PubMed  CAS  Google Scholar 

  • Cortright RN, Collins HL, Chandler MP, Lemon PW, DiCarlo SE (1996) Diabetes reduces growth and body composition more in male than in female rats. Physiol Behav 60:1233–1238

    Article  PubMed  CAS  Google Scholar 

  • De Bisschop E, Luypaert R, Louis O, Osteaux M (1993) Fat fraction of lumbar bone marrow using in vivo proton nuclear magnetic resonance spectroscopy. Bone 14:133–136

    Article  PubMed  Google Scholar 

  • Flanagan DE, Vaile JC, Petley GW, Phillips DI, Godsland IF, Owens P, Moore VM, Cockington RA, Robinson JS (2007) Gender differences in the relationship between leptin, insulin resistance and the autonomic nervous system. Regul Pept 140:37–42

    Article  PubMed  CAS  Google Scholar 

  • Frenkel B, Capparelli C, Van Auken M, Baran D, Bryan J, Stein JL, Stein GS, Lian JB (1997) Activity of the osteocalcin promoter in skeletal sites of transgenic mice and during osteoblast differentiation in bone marrow-derived stromal cell cultures: effects of age and sex. Endocrinology 138:2109–2116

    Article  PubMed  CAS  Google Scholar 

  • Gale EA (2002) The rise of childhood type 1 diabetes in the 20th century. Diabetes 51:3353–3361

    Article  PubMed  CAS  Google Scholar 

  • Gillespie KM, Bain SC, Barnett AH, Bingley PJ, Christie MR, Gill GV, Gale EA (2004) The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes. Lancet 364:1699–1700

    Article  PubMed  Google Scholar 

  • Gimble JM, Zvonic S, Floyd ZE, Kassem M, Nuttall ME (2006) Playing with bone and fat. J Cell Biochem 98:251–266

    Article  PubMed  CAS  Google Scholar 

  • Goodman WG, Hori MT (1984) Diminished bone formation in experimental diabetes. Relationship to osteoid maturation and mineralization. Diabetes 33:825–831

    Article  PubMed  CAS  Google Scholar 

  • Griffith JF, Yeung DK, Antonio GE, Wong SY, Kwok TC, Woo J, Leung PC (2006) Vertebral marrow fat content and diffusion and perfusion indexes in women with varying bone density: MR evaluation. Radiology 241:831–838

    Article  PubMed  Google Scholar 

  • Hadjidakis DJ, Raptis AE, Sfakianakis M, Mylonakis A, Raptis SA (2006) Bone mineral density of both genders in Type 1 diabetes according to bone composition. J Diabetes Complicat 20:302–307

    Article  PubMed  Google Scholar 

  • Hamrick MW, Pennington C, Newton D, Xie D, Isales C (2004) Leptin deficiency produces contrasting phenotypes in bones of the limb and spine. Bone 34:376–383

    Article  PubMed  CAS  Google Scholar 

  • Harrison JR, Kleinert LM, Kelly PL, Krebsbach PH, Woody C, Clark S, Rowe DW, Lichtler AC, Kream BE (1998) Interleukin-1 represses COLIA1 promoter activity in calvarial bones of transgenic ColCAT mice in vitro and in vivo. J Bone Miner Res 13:1076–1083

    Article  PubMed  CAS  Google Scholar 

  • Hernandez C, Lecube A, Castellanos JM, Segura RM, Garat M, Garcia-Arumi J, Simo R (2004) Intravitreous leptin concentrations in patients with proliferative diabetic retinopathy. Retina 24:30–35

    Article  PubMed  Google Scholar 

  • Herrero S, Calvo OM, Garcia-Moreno C, Martin E, San Roman JI, Martin M, Garcia-Talavera JR, Calvo JJ, del Pino-Montes J (1998) Low bone density with normal bone turnover in ovariectomized and streptozotocin-induced diabetic rats. Calcif Tissue Int 62:260–265

    Article  PubMed  CAS  Google Scholar 

  • Hodges P, Holm AK, Hansson T, Holm S (2006) Rapid atrophy of the lumbar multifidus follows experimental disc or nerve root injury. Spine 31:2926–2933

    Article  PubMed  Google Scholar 

  • Ikegame M, Ishibashi O, Yoshizawa T, Shimomura J, Komori T, Ozawa H, Kawashima H (2001) Tensile stress induces bone morphogenetic protein 4 in preosteoblastic and fibroblastic cells, which later differentiate into osteoblasts leading to osteogenesis in the mouse calvariae in organ culture. J Bone Miner Res 16:24–32

    Article  PubMed  CAS  Google Scholar 

  • Jee WS, Wronski TJ, Morey ER, Kimmel DB (1983) Effects of spaceflight on trabecular bone in rats. Am J Physiol 244:R310–R314

    PubMed  CAS  Google Scholar 

  • Jenis LG, Ongphiphadhanakul B, Braverman LE, Stein GS, Lian JB, Lew R, Baran DT (1994) Responsiveness of gene expression markers of osteoblastic and osteoclastic activity to calcitonin in the appendicular and axial skeleton of the rat in vivo. Calcif Tissue Int 54:511–515

    Article  PubMed  CAS  Google Scholar 

  • Jiang J, Lichtler AC, Gronowicz GA, Adams DJ, Clark SH, Rosen CJ, Kream BE (2006) Transgenic mice with osteoblast-targeted insulin-like growth factor-I show increased bone remodeling. Bone 39(3):494–504

    Article  PubMed  CAS  Google Scholar 

  • Kaji H, Tobimatsu T, Naito J, Iu MF, Yamauchi M, Sugimoto T, Chihara K (2006) Body composition and vertebral fracture risk in female patients treated with glucocorticoid. Osteoporos Int 17:627–633

    Article  PubMed  CAS  Google Scholar 

  • Karaguzel G, Ozdem S, Boz A, Bircan I, Akcurin S (2006) Leptin levels and body composition in children and adolescents with type 1 diabetes. Clin Biochem 39:788–793

    Article  PubMed  CAS  Google Scholar 

  • Kemink SA, Hermus AR, Swinkels LM, Lutterman JA, Smals AG (2000) Osteopenia in insulin-dependent diabetes mellitus; prevalence and aspects of pathophysiology. J Endocrinol Invest 23:295–303

    PubMed  CAS  Google Scholar 

  • Kiess W, Anil M, Blum WF, Englaro P, Juul A, Attanasio A, Dotsch J, Rascher W (1998) Serum leptin levels in children and adolescents with insulin-dependent diabetes mellitus in relation to metabolic control and body mass index. Eur J Endocrinol 138:501–509

    Article  PubMed  CAS  Google Scholar 

  • Krakauer JC, McKenna MJ, Buderer NF, Rao DS, Whitehouse FW, Parfitt AM (1995) Bone loss and bone turnover in diabetes. Diabetes 44:775–782

    Article  PubMed  CAS  Google Scholar 

  • Kratzsch J, Deimel A, Galler A, Kapellen T, Klinghammer A, Kiess W (2004) Increased serum soluble leptin receptor levels in children and adolescents with type 1 diabetes mellitus. Eur J Endocrinol 151:475–481

    Article  PubMed  CAS  Google Scholar 

  • Kream BE, Smith MD, Canalis E, Raisz LG (1985) Characterization of the effect of insulin on collagen synthesis in fetal rat bone. Endocrinology 116:296–302

    Article  PubMed  CAS  Google Scholar 

  • Levin ME, Boisseau VC, Avioli LV (1976) Effects of diabetes mellitus on bone mass in juvenile and adult-onset diabetes. N Engl J Med 294:241–245

    Article  PubMed  CAS  Google Scholar 

  • Li X, Cui Q, Kao C, Wang GJ, Balian G (2003) Lovastatin inhibits adipogenic and stimulates osteogenic differentiation by suppressing PPARgamma2 and increasing Cbfa1/Runx2 expression in bone marrow mesenchymal cell cultures. Bone 33:652–659

    Article  PubMed  CAS  Google Scholar 

  • Lo HC, Lin SC, Wang YM (2004) The relationship among serum cytokines, chemokine, nitric oxide, and leptin in children with type 1 diabetes mellitus. Clin Biochem 37:666–672

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Ibarra PJ, Pastor MM, Escobar-Jimenez F, Pardo MD, Gonzalez AG, Luna JD, Requena ME, Diosdado MA (2001) Bone mineral density at time of clinical diagnosis of adult-onset type 1 diabetes mellitus. Endocr Pract 7:346–351

    PubMed  CAS  Google Scholar 

  • McCauley LK, Koh-Paige AJ, Chen H, Chen C, Ontiveros C, Irwin R, McCabe LR (2001) Parathyroid hormone stimulates fra-2 expression in osteoblastic cells in vitro and in vivo. Endocrinology 142:1975–1981

    Article  PubMed  CAS  Google Scholar 

  • McCracken M, Lemons JE, Rahemtulla F, Prince CW, Feldman D (2000) Bone response to titanium alloy implants placed in diabetic rats. Int J Oral Maxillofac Implants 15:345–354

    PubMed  CAS  Google Scholar 

  • Miao J, Brismar K, Nyren O, Ugarph-Morawski A, Ye W (2005) Elevated hip fracture risk in type 1 diabetic patients: a population-based cohort study in Sweden. Diabetes Care 28:2850–2855

    Article  PubMed  Google Scholar 

  • Moerman EJ, Teng K, Lipschitz DA, Lecka-Czernik B (2004) Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-gamma2 transcription factor and TGF-beta/BMP signaling pathways. Aging Cell 3:379–389

    Article  PubMed  CAS  Google Scholar 

  • Munoz-Torres M, Jodar E, Escobar-Jimenez F, Lopez-Ibarra PJ, Luna JD (1996) Bone mineral density measured by dual X-ray absorptiometry in Spanish patients with insulin-dependent diabetes mellitus. Calcif Tissue Int 58:316–319

    Article  PubMed  CAS  Google Scholar 

  • Oyster N (1992) Sex differences in cancellous and cortical bone strength, bone mineral content and bone density. Age Ageing 21:353–356

    Article  PubMed  CAS  Google Scholar 

  • Pechhold K, Patterson NB, Blum C, Fleischacker CL, Boehm BO, Harlan DM (2001) Low dose streptozotocin-induced diabetes in rat insulin promoter-mCD80-transgenic mice is T cell autoantigen-specific and CD28 dependent. J Immunol 166:2531–2539

    PubMed  CAS  Google Scholar 

  • Reid IR (2002) Relationships among body mass, its components, and bone. Bone 31:547–555

    Article  PubMed  CAS  Google Scholar 

  • Reid IR (2004) Leptin deficiency-lessons in regional differences in the regulation of bone mass. Bone 34:369–371

    Article  PubMed  CAS  Google Scholar 

  • Riggs BL, Melton LJ 3rd, Robb RA, Camp JJ, Atkinson EJ, Peterson JM, Rouleau PA, McCollough CH, Bouxsein ML, Khosla S (2004) Population-based study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites. J Bone Miner Res 19:1945–1954

    Article  PubMed  Google Scholar 

  • Rosen CJ, Bouxsein ML (2006) Mechanisms of disease: is osteoporosis the obesity of bone? Nat Clin Pract Rheumatol 2:35–43

    Article  PubMed  CAS  Google Scholar 

  • Rosen CJ, Ackert-Bicknell CL, Adamo ML, Shultz KL, Rubin J, Donahue LR, Horton LG, Delahunty KM, Beamer WG, Sipos J, Clemmons D, Nelson T, Bouxsein ML, Horowitz M (2004) Congenic mice with low serum IGF-I have increased body fat, reduced bone mineral density, and an altered osteoblast differentiation program. Bone 35:1046–1058

    Article  PubMed  CAS  Google Scholar 

  • Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, Bouali Y, Mukhopadhyay K, Ford K, Nestler EJ, Baron R (2000) Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis [see comments]. Nat Med 6:985–990

    Article  PubMed  CAS  Google Scholar 

  • Santana RB, Xu L, Chase HB, Amar S, Graves DT, Trackman PC (2003) A role for advanced glycation end products in diminished bone healing in type 1 diabetes. Diabetes 52:1502–1510

    Article  PubMed  CAS  Google Scholar 

  • Sasaki T, Kaneko H, Ramamurthy NS, Golub LM (1991) Tetracycline administration restores osteoblast structure and function during experimental diabetes. Anat Rec 231:25–34

    Article  PubMed  CAS  Google Scholar 

  • Schneider CP, Schwacha MG, Chaudry IH (2006) Impact of gender and age on bone marrow immune responses in a murine model of trauma-hemorrhage. J Appl Physiol 102(1):113–121

    Article  PubMed  CAS  Google Scholar 

  • Shyng YC, Devlin H, Sloan P (2001) The effect of streptozotocin-induced experimental diabetes mellitus on calvarial defect healing and bone turnover in the rat. Int J Oral Maxillofac Surg 30:70–74

    Article  PubMed  CAS  Google Scholar 

  • Strotmeyer ES, Cauley JA, Orchard TJ, Steenkiste AR, Dorman JS (2006) Middle-aged premenopausal women with type 1 diabetes have lower bone mineral density and calcaneal quantitative ultrasound than nondiabetic women. Diabetes Care 29:306–311

    Article  PubMed  Google Scholar 

  • Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 50:537–546

    PubMed  CAS  Google Scholar 

  • Taaffe DR, Lang TF, Fuerst T, Cauley JA, Nevitt MC, Harris TB (2003) Sex- and race-related differences in cross-sectional geometry and bone density of the femoral mid-shaft in older adults. Ann Hum Biol 30:329–346

    Article  PubMed  CAS  Google Scholar 

  • Takeshita F, Iyama S, Ayukawa Y, Kido MA, Murai K, Suetsugu T (1997) The effects of diabetes on the interface between hydroxyapatite implants and bone in rat tibia. J Periodontol 68:180–185

    PubMed  CAS  Google Scholar 

  • Tam J, Ofek O, Fride E, Ledent C, Gabet Y, Muller R, Zimmer A, Mackie K, Mechoulam R, Shohami E, Bab I (2006) Involvement of neuronal cannabinoid receptor CB1 in regulation of bone mass and bone remodeling. Mol Pharmacol 70:786–792

    Article  PubMed  CAS  Google Scholar 

  • Thrailkill KM, Fowlkes JL, Hyde JF, Litton JC (2001) The effects of co-therapy with recombinant human insulin-like growth factor I and insulin on serum leptin levels in adolescents with type 1 diabetes mellitus. Pediatr Diabetes 2:25–29

    Article  PubMed  CAS  Google Scholar 

  • Thrailkill KM, Liu L, Wahl EC, Bunn RC, Perrien DS, Cockrell GE, Skinner RA, Hogue WR, Carver AA, Fowlkes JL, Aronson J, Lumpkin CK Jr (2005) Bone formation is impaired in a model of type 1 diabetes. Diabetes 54:2875–2881

    Article  PubMed  CAS  Google Scholar 

  • Tuominen JT, Impivaara O, Puukka P, Ronnemaa T (1999) Bone mineral density in patients with type 1 and type 2 diabetes. Diabetes Care 22:1196–1200

    Article  PubMed  CAS  Google Scholar 

  • Verhaeghe J, van Herck E, Visser WJ, Suiker AM, Thomasset M, Einhorn TA, Faierman E, Bouillon R (1990) Bone and mineral metabolism in BB rats with long-term diabetes. Decreased bone turnover and osteoporosis. Diabetes 39:477–482

    Article  PubMed  CAS  Google Scholar 

  • Verhaeghe J, Thomsen JS, van Bree R, van Herck E, Bouillon R, Mosekilde L (2000) Effects of exercise and disuse on bone remodeling, bone mass, and biomechanical competence in spontaneously diabetic female rats. Bone 27:249–256

    Article  PubMed  CAS  Google Scholar 

  • Verma S, Rajaratnam JH, Denton J, Hoyland JA, Byers RJ (2002) Adipocytic proportion of bone marrow is inversely related to bone formation in osteoporosis. J Clin Pathol 55:693–698

    Article  PubMed  CAS  Google Scholar 

  • Wallace JM, Rajachar RM, Chen XD, Shi S, Allen MR, Bloomfield SA, Les CM, Robey PG, Young MF, Kohn DH (2006) The mechanical phenotype of biglycan-deficient mice is bone- and gender-specific. Bone 39:106–116

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Sakata T, Elalieh HZ, Munson SJ, Burghardt A, Majumdar S, Halloran BP, Bikle DD (2006) Gender differences in the response of CD-1 mouse bone to parathyroid hormone: potential role of IGF-I. J Endocrinol 189:279–287

    Article  PubMed  CAS  Google Scholar 

  • Weiss LA, Barrett-Connor E, von Muhlen D, Clark P (2006) Leptin predicts BMD and bone resorption in older women but not older men: the Rancho Bernardo study. J Bone Miner Res 21:758–764

    Article  PubMed  CAS  Google Scholar 

  • Woitge HW, Kream BE (2000) Calvariae from fetal mice with a disrupted Igf1 gene have reduced rates of collagen synthesis but maintain responsiveness to glucocorticoids. J Bone Miner Res 15:1956–1964

    Article  PubMed  CAS  Google Scholar 

  • Yamauchi M, Sugimoto T, Yamaguchi T, Nakaoka D, Kanzawa M, Yano S, Ozuru R, Sugishita T, Chihara K (2001) Plasma leptin concentrations are associated with bone mineral density and the presence of vertebral fractures in postmenopausal women. Clin Endocrinol (Oxf) 55:341–347

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the Investigative Histology Laboratory in the Department of Physiology, Division of Human Pathology at Michigan State University for assistance with the histological studies, and Regina Irwin, Sergiu Botolin and Katie Motyl for their technical expertise and assistance with diabetic mice and analyses, and Gavin Gibson and Laura Harris for their critical review of this manuscript. This work was funded by a grant from NIH (DK061184) to LRM.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Laura R. McCabe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martin, L.M., McCabe, L.R. Type I diabetic bone phenotype is location but not gender dependent. Histochem Cell Biol 128, 125–133 (2007). https://doi.org/10.1007/s00418-007-0308-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-007-0308-4

Keywords

Navigation