Advertisement

Medical Molecular Morphology

, Volume 51, Issue 3, pp 139–146 | Cite as

Morphological and molecular characterization of the senile osteoporosis in senescence-accelerated mouse prone 6 (SAMP6)

  • Kagaku Azuma
  • Qian Zhou
  • Kin-ya Kubo
Review

Abstract

Although the understanding of the complex pathogenesis for osteoporosis is appreciable, the underlying mechanism is not yet fully elucidated. There is a great need to further characterize the available animal models in osteoporosis research. The senescence-accelerated mouse prone 6 (SAMP6) mice have been developed as the spontaneous experimental model for senile osteoporosis. Here, we provide a comprehensive overview of current research regarding the bone morphological and molecular alterations and the possible mechanisms involved in these changes. There were significant decrease in trabecular bone mass at the axial and appendicular skeletal sites, with no marked alterations of cortical bone. Decreased bone formation on the endosteal surface and trabecular bone, and increased bone marrow adiposity were observed in SAMP6 mice. The elevated expression level of proliferator activator gamma (PPARγ) in the bone marrow suggest that PPARγ might regulate osteoblastic bone formation negatively in SAMP6 mice. The expression level of secreted frizzled-related protein 4 (Sfrp4) was found to be higher in SAMP6 mice. Sfrp4 is considered to suppress osteoblastic proliferation mediated by inhibition of Wnt signaling pathway. These findings may help us to gain more insight into the potential mechanism of senile osteoporosis.

Keywords

SAMP6 Osteoporosis Bone structure PPARγ sFRP4 

References

  1. 1.
    Chen H, Senda T, Kubo KY (2015) The osteocyte plays multiple roles in bone remodeling and mineral homeostasis. Med Mol Morphol 48:61–68CrossRefPubMedGoogle Scholar
  2. 2.
    Chen H, Zhou X, Fujita H, Onozuka M, Kubo KY (2013) Age-related changes in trabecular and cortical bone microstructure. Int J Endocrinol 2013:213234PubMedPubMedCentralGoogle Scholar
  3. 3.
    Kalu DN (1991) The ovariectomized rat model of postmenopausal bone loss. Bone Miner 15:175–191CrossRefPubMedGoogle Scholar
  4. 4.
    Kalu DN, Chen C (1999) Ovariectomized murine model of postmenopausal calcium malabsorption. J Bone Miner Res 14:593–601CrossRefPubMedGoogle Scholar
  5. 5.
    Kharode YP, Sharp MC, Bodine PV (2008) Utility of the ovariectomized rat as a model for human osteoporosis in drug discovery. Methods Mol Biol 455:111–124CrossRefPubMedGoogle Scholar
  6. 6.
    Priemel M, Schilling AF, Haberland M, Pogoda P, Rueger JM, Amling M (2002) Osteopenic mice: animal models of the aging skeleton. J Musculoskelet Neuronal Interact 2:212–218PubMedGoogle Scholar
  7. 7.
    Watanabe K, Hishiya A (2005) Mouse models of senile osteoporosis. Mol Asp Med 26:221–231CrossRefGoogle Scholar
  8. 8.
    Takeda T, Hosokawa M, Takeshita S, Irino M, Higuchi K, Matsushita T, Tomita Y, Yasuhira K, Hamamoto H, Shimizu K, Ishii M, Yamamuro T (1981) A new murine model of accelerated senescence. Mech Ageing Dev 17:183–194CrossRefPubMedGoogle Scholar
  9. 9.
    Takeda T, Hosokawa M, Higuchi K (1991) Senescence-accelerated mouse (SAM): a new murine model of accelerated senescence. J Am Geriatr Soc 39:911–919CrossRefPubMedGoogle Scholar
  10. 10.
    Takeda T, Matsushita Kurozumi M (1997) Pathobiology of the senescence-accelerated mouse (SAM). Exp Gerontol 32:117–127CrossRefPubMedGoogle Scholar
  11. 11.
    Xia C, Higuchi K, Shimizu M et al (1999) Genetic typing of the senescence-accelerated mouse (SAM) strains with microsatellite markers. Mamm Genome 10:235–238CrossRefPubMedGoogle Scholar
  12. 12.
    Matsushita M, Tsuboyama T, Kasai R, Okumura H, Yamamuro T, Higuchi K, Kohno A, Umezawa M, Takeda T (1986) Age-related changes in bone mass in the senescence-accelerated mouse (SAM): SAM-R/3 and SAM-P/6 as new murine models for senile osteoporosis. Am J Pathol 125:276–283PubMedPubMedCentralGoogle Scholar
  13. 13.
    Jilka RL, Weinstein RS, Takahashi K, Parfitt AM, Manolagas SC (1996) Linkage of decreased bone mass with impaired osteoblastogenesis in a murine model of accelerated senescence. J Clin Invest 97:1732–1740CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Chen H, Shoumura S, Emura S (2004) Ultrastructural changes in bones of the senescence-accelerated mouse (SAMP6): a murine model for senile osteoporosis. Histol Histopathol 19:677–685PubMedGoogle Scholar
  15. 15.
    Niimi K, Takahashi E, Itakura C (2009) Adiposity-related biochemical phenotype in senescence-accelerated mouse prone 6 (SAMP6). Comp Med 59:431–436PubMedPubMedCentralGoogle Scholar
  16. 16.
    Liu CZ, Yu JC, Cheng HY, Jiang ZG, Li T, Zhang XZ, Zhang LL, Han JX (2006) Spatial memory performance and hippocampal neuron number in osteoporotic SAMP6 mice. Exp Neurol 201:452–460CrossRefPubMedGoogle Scholar
  17. 17.
    Niimi K, Takahashi E, Itakura C (2008) Emotional behavior and expression patterns of tyrosine hydroxylase and tryptophan hydroxylase in senescence-accelerated mouse (SAM) P6 mice. Behav Brain Res 188:329–336CrossRefPubMedGoogle Scholar
  18. 18.
    Chen H, Emura S, Yao XF, Shoumura S (2004) Morphological study of the parathyroid gland and thyroid C cell in senescence-accelerated mouse (SAMP6), a murine model for senile osteoporosis. Tissue Cell 36:409–415CrossRefPubMedGoogle Scholar
  19. 19.
    Chen H, Emura S, Shoumura S (2006) Ultrastructure of the water-clear cell in the parathyroid gland of SAMP6 mice. Tissue Cell 38:187–192CrossRefPubMedGoogle Scholar
  20. 20.
    Chen H, Yao XF, Emura S, Shoumura S (2006) Morphological changes of skeletal muscle, tendon and periosteum in the senescence-accelerated mouse (SAMP6): a murine model for senile osteoporosis. Tissue Cell 38:325–335CrossRefPubMedGoogle Scholar
  21. 21.
    Chen H, Zhou X, Emura S, Shoumura S (2009) Site-specific bone loss in senescence-accelerated mouse (SAMP6): a murine model for senile osteoporosis. Exp Gerontol 44:792–798CrossRefPubMedGoogle Scholar
  22. 22.
    Chen H, Kubo KY (2012) Segmental variations in trabecular bone density and microstructure of the spine in senescence-accelerated mouse (SAMP6): a murine model for senile osteoporosis. Exp Gerontol 47:317–322CrossRefPubMedGoogle Scholar
  23. 23.
    Chen H, Emura S, Isono H, Shoumura S (2005) Effects of traditional Chinese medicine on bone loss in SAMP6: a murine model for senile osteoporosis. Biol Pharm Bull 28:865–869CrossRefPubMedGoogle Scholar
  24. 24.
    Silva MJ, Brodt MD, Wopenka B, Thomopoulos S, Williams D, Wassen MH, Ko M, Kusano N, Bank RA (2006) Decreased collagen organization and content are associated with reduced strength of demineralized and intact bone in the SAMP6 mouse. J Bone Miner Res 21:78–88CrossRefPubMedGoogle Scholar
  25. 25.
    Silva MJ, Brodt MD, Ko M, Abu-Amer Y (2005) Impaired marrow osteogenesis is associated with reduced endocortical bone formation but does not impair periosteal bone formation in long bones of SAMP6 mice. J Bone Miner Res 20:419–427CrossRefPubMedGoogle Scholar
  26. 26.
    Tokutomi K, Matsuura T, Atsawasuwan P, Sato H, Yamauchi M (2008) Characterization of mandibular bones in senile osteoporotic mice. Connect Tissue Res 49:361–366CrossRefPubMedGoogle Scholar
  27. 27.
    Ganguly P, El-Jawhari JJ, Giannoudis PV, Burska AN, Ponchel F, Jones EA (2017) Age-related changes in bone marrow mesenchymal stromal cells: a potential impact on osteoporosis and osteoarthritis development. Cell Transpl 26:1520–1529CrossRefGoogle Scholar
  28. 28.
    Bethel M, Chitteti BR, Srour EF, Kacena MA (2013) The changing balance between osteoblastogenesis and adipogenesis in aging and its impact on hematopoiesis. Curr Osteoporos Rep 11:99–106CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Liu H, Xia X, Li B (2015) Mesenchymal stem cell aging: mechanisms and influences on skeletal and non-skeletal tissues. Exp Biol Med (Maywood) 240:1099–1106CrossRefGoogle Scholar
  30. 30.
    Ichioka N, Inaba M, Kushida T, Esumi T, Takahara K, Inaba K, Ogawa R, Iida H, Ikehara S (2002) Prevention of senile osteoporosis in SAMP6 mice by intrabone marrow injection of allogeneic bone marrow cells. Stem Cells 20:542–551CrossRefPubMedGoogle Scholar
  31. 31.
    Takada K, Inaba M, Ichioka N, Ueda Y, Taira M, Baba S, Mizokami T, Wang X, Hisha H, Iida H, Ikehara S (2006) Treatment of senile osteoporosis in SAMP6 mice by intra-bone marrow injection of allogeneic bone marrow cells. Stem Cells 24:399–405CrossRefPubMedGoogle Scholar
  32. 32.
    Ueda Y, Inaba M, Takada K, Fukui J, Sakaguchi Y, Tsuda M, Omae M, Kushida T, Iida H, Ikehara S (2007) Induction of senile osteoporosis in normal mice by intra-bone marrow-bone marrow transplantation from osteoporosis-prone mice. Stem Cells 25:1356–1363CrossRefPubMedGoogle Scholar
  33. 33.
    Kajkenova O, Lecka-Czernik B, Gubrij I, Hauser SP, Takahashi K, Parfitt AM, Jilka RL, Manolagas SC, Lipschitz DA (1997) Increased adipogenesis and myelopoiesis in the bone marrow of SAMP6, a murine model of defective osteoblastogenesis and low turnover osteopenia. J Bone Miner Res 12:1772–1779CrossRefPubMedGoogle Scholar
  34. 34.
    Sui B, Hu C, Liao L, Chen Y, Zhang X, Fu X, Zheng C, Li M, Wu L, Zhao X, Jin Y (2016) Mesenchymal progenitors in osteopenias of diverse pathologies: differential characteristics in the common shift from osteoblastogenesis to adipogenesis. Sci Rep 6:30186CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Cao J, Ou G, Yang N, Ding K, Kream BE, Hamrick MW, Isales CM, Shi XM (2015) Impact of targeted PPARγ disruption on bone remodeling. Mol Cell Endocrinol 410:27–34CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Sun H, Kim JK, Mortensen R, Mutyaba LP, Hankenson KD, Krebsbach PH (2013) Osteoblast-targeted suppression of PPARγ increases osteogenesis through activation of mTOR signaling. Stem Cells 31:2183–2192CrossRefPubMedGoogle Scholar
  37. 37.
    Meunier P, Aaron J, Edouard C, Vignon G (1971) Osteoporosis and the replacement of cell populations of the marrow by adipose tissue. A quantitative study of 84 iliac bone biopsies. Clin Orthop Relat Res 80:147–154CrossRefPubMedGoogle Scholar
  38. 38.
    Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM (1999) PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 4:611–617CrossRefPubMedGoogle Scholar
  39. 39.
    Tsuboyama T, Takahashi K, Matsushita M, Okumura H, Yamamuro T, Umezawa M, Takeda T (1989) Decreased endosteal formation during cortical bone modelling in SAM-P/6 mice with a low peak bone mass. Bone Miner 7:1–12CrossRefPubMedGoogle Scholar
  40. 40.
    Tsuboyama T, Takahashi K, Yamamuro T, Hosokawa M, Takeda T (1993) Cross-mating study on bone mass in the spontaneously osteoporotic mouse (SAM-P/6). Bone Miner 23:57–64CrossRefPubMedGoogle Scholar
  41. 41.
    Shimizu M, Higuchi K, Bennett B, Xia C, Tsuboyama T, Kasai S, Chiba T, Fujisawa H, Kogishi K, Kitado H, Kimoto M, Takeda N, Matsushita M, Okumura H, Serikawa T, Nakamura T, Johnson TE, Hosokawa M (1999) Identification of peak bone mass QTL in a spontaneously osteoporotic mouse strain. Mamm Genome 10:81–87CrossRefPubMedGoogle Scholar
  42. 42.
    Otsuki B, Matsumura T, Shimizu M, Mori M, Okudaira S, Nakanishi R, Higuchi K, Hosokawa M, Tsuboyama T, Nakamura T (2007) Quantitative trait locus that determines the cross-sectional shape of the femur in SAMP6 and SAMP2 mice. J Bone Miner Res 22:675–685CrossRefPubMedGoogle Scholar
  43. 43.
    Okudaira S, Shimizu M, Otsuki B, Nakanishi R, Ohta A, Higuchi K, Hosokawa M, Tsuboyama T, Nakamura T (2010) Quantitative trait locus on chromosome X affects bone loss after maturation in mice. J Bone Miner Metab 28:520–531CrossRefPubMedGoogle Scholar
  44. 44.
    Nakanishi R, Shimizu M, Mori M, Akiyama H, Okudaira S, Otsuki B, Hashimoto M, Higuchi K, Hosokawa M, Tsuboyama T, Nakamura T (2006) Secreted frizzled-related protein 4 is a negative regulator of peak BMD in SAMP6 mice. J Bone Miner Res 21:1713–1721CrossRefPubMedGoogle Scholar
  45. 45.
    Nakanishi R, Akiyama H, Kimura H, Otsuki B, Shimizu M, Tsuboyama T, Nakamura T (2008) Osteoblast-targeted expression of Sfrp4 in mice results in low bone mass. J Bone Miner Res 23:271–277CrossRefPubMedGoogle Scholar
  46. 46.
    Haraguchi R, Kitazawa R, Mori K, Tachibana R, Kiyonari H, Imai Y, Abe T, Kitazawa S (2016) sFRP4-dependent Wnt signal modulation is critical for bone remodeling during postnatal development and age-related bone loss. Sci Rep 6:25198CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Lee DY, Kim H, Ku SY, Kim SH, Choi YM, Kim JG (2010) Association between polymorphisms in Wnt signaling pathway genes and bone mineral density in postmenopausal Korean women. Menopause 17:1064–1070CrossRefPubMedGoogle Scholar
  48. 48.
    Fujita M, Urano T, Shiraki M, Momoeda M, Tsutsumi O, Hosoi T, Orimo H, Ouchi Y, Inoue S (2004) Association of a single nucleotide polymorphism in the secreted frizzled-related protein 4 (sFRP4) gene with bone mineral density. Geriatr Gerontol Int 4:175–180CrossRefGoogle Scholar
  49. 49.
    Clément-Lacroix P, Ai M, Morvan F, Roman-Roman S, Vayssière B, Belleville C, Estrera K, Warman ML, Baron R, Rawadi G (2005) Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc Natl Acad Sci USA 102:17406–17411CrossRefPubMedGoogle Scholar
  50. 50.
    Chen X, Li L, Guo J, Zhang L, Yuan Y, Chen B, Sun Z, Xu J, Zou J (2016) Treadmill running exercise prevents senile osteoporosis and upregulates the Wnt signaling pathway in SAMP6 mice. Oncotarget 7:71072–71086PubMedPubMedCentralGoogle Scholar
  51. 51.
    Kramer I, Halleux C, Keller H, Pegurri M, Gooi JH, Weber PB, Feng JQ, Bonewald LF, Kneissel M (2010) Osteocyte Wnt/β-catenin signaling is required for normal bone homeostasis. Mol Cell Biol 30:3071–3085CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    MacDonald BT, Tamai K, He X (2009) Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev Cell 17:9–26CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Baron R, Kneissel M (2013) Wnt signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192CrossRefPubMedGoogle Scholar
  54. 54.
    Beighton P (1987) Pyle disease (metaphyseal dysplasia. J Med Genet 24:321–324CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Galada C, Shah H, Shukla A, Girisha KM (2017) A novel sequence variant in SFRP4 causing Pyle disease. J Hum Genet 62:575–576CrossRefPubMedGoogle Scholar
  56. 56.
    Kiper POS, Saito H, Gori F, Unger S, Hesse E, Yamana K, Kiviranta R, Solban N, Liu J, Brommage R, Boduroglu K, Bonafé L, Campos-Xavier B, Dikoglu E, Eastell R, Gossiel F, Harshman K, Nishimura G, Girisha KM, Stevenson BJ, Takita H, Rivolta C, Superti-Furga A, Baron R (2016) Cortical-bone fragility—insights from sFRP4 deficiency in Pyle’s disease. N Engl J Med 374:2553–2562CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Chen H, Zhou X, Shoumura S, Emura S, Bunai Y (2010) Age- and gender-dependent changes in three-dimensional microstructure of cortical and trabecular bone at the human femoral neck. Osteoporos Int 21:627–636CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society for Clinical Molecular Morphology 2018

Authors and Affiliations

  1. 1.Department of Anatomy, School of MedicineUniversity of Occupational and Environmental HealthKitakyushuJapan
  2. 2.Department of Food Science and Nutrition, Faculty of Human Life and Environmental ScienceNagoya Women’s UniversityNagoyaJapan

Personalised recommendations