Abstract
Our understanding of the developmental biology of the skeleton, like that of virtually every other subject in biology, has been transformed by recent advances in human and mouse genetics, but we still know very little, in molecular and genetic terms, about skeletal physiology. Thus, among the many questions that are largely unexplained are the following: why is osteoporosis mainly a women’s disease? How is bone mass maintained nearly constant between the end of puberty and the arrest of gonadal functions? Molecular genetics has emerged as a powerful tool to study previously unexplored aspects of the physiology of the skeleton. Among mammals, mice are the most promising animals for this experimental work. The input that transgenic animals can offer to our field depends on our means of phenotypic characterization of the mouse skeleton. In fact, full appreciation of the skeletal characteristics of a given mouse model requires the application of standardized protocols for noninvasive imaging, histology, histomorphometry, biomechanics, and individually adapted in vitro and in vivo analysis. Over the past years we have established a mouse archive that consists of 14839 cases from more than 120 different mouse models that we have phenotypically characterized in Hamburg. Today, this is one of the biggest databases on the mouse skeleton. This review focuses on one aspect of skeletal physiology, namely skeletal aging, and demonstrates that mouse models can be a valuable tool to gain insights in certain facets of skeletal physiology that have been unexplored previously.
Similar content being viewed by others
References
Frost HM, Jee WS (1992) On the rat model of human osteopenias and osteoporoses. Bone Miner 18: 227–236
Miller SC, Bowman BM, Jee WS (1995) Available animal models of osteopenia — small and large. Bone 17: 117S-123S
Jee WS, Ma Y (1999) Animal models of immobilization osteopenia. Morphologie 83: 25–34
Rubin J, Rubin H, Rubin C (1999) Constraints of experimental paradigms used to model the aging skeleton. In: Rosen CJ, Glowacki J, Bilezikian JP (eds) The Aging Skeleton. Academic, San Diego, pp 27–36
Kalu DN (1999) Animal models of the aging skeleton. In: Rosen CJ, Glowacki J, Bilezikian JP (eds) The Aging Skeleton. Academic, San Diego, pp 37–50
Soriano P, Montgomery C, Geske R, Bradley A (1991) Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64: 693–702
Felix R, Hofstetter W, Cecchini MG (1996) Recent developments in the understanding of the pathophysiology of osteopetrosis. Eur J Endocrinol 134: 143–156
Amling M, Neff L, Priemel M, Schilling AF, Rueger JM, Baron R (2000) Progressive osteopetrosis and development of odontomas in aging c-Src deficient mice. Bone 27: 603–610
Amizuka N, Warshawsky H, Henderson JE, Goltzman D, Karaplis AC (1994) Parathyroid hormone-related peptide-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation. J Cell Biol 126: 1611–1623
Lanske B, Karaplis AC, Lee K, Luz A, Vortkamp A, Pirro A, Karperien M, Defize LH, Ho C, Mulligan RC, Abou-Samra AB, Juppner H, Segre GV, Kronenberg HM (1996) PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273: 663–666
Amling M, Neff L, Tanaka S, Inoue D, Kuida K, Weir E, Philbrick WM, Broadus AE, Baron R (1997) Bcl-2 lies downstream of parathyroid hormone-related peptide in a signaling pathway that regulates chondrocyte maturation during skeletal development. J Cell Biol 136: 205–213
Lanske B, Amling M, Neff L, Guiducci J, Baron R, Kronenberg HM (1999) Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development. J Clin Invest 104: 399–407
Schilling AF, Priemel M, Beil FT, Haberland M, Holzmann T, Català-Lehnen P, Pogoda P, Blicharski D, Müldner C, Löcherbach C, Rueger JM, Amling M (2001) Transgenic mice in skeletal research. Towards a molecular understanding of the mammalian skeleton. J Musculoskel Neuronal Interact 1: 275–289
Ornoy A, Katzburg S (1995) Osteoporosis: animal models for human disease. In: Ornoy A (ed) Animal Models of Human Related Calcium Disorders. CRC, New York, pp 105–126
Kimmel DB (1996) Animal models for in vivo experimentation in osteoporosis research. In: Marcus R, Feldman D, Kelsey J (eds) Osteoporosis. Academic, New York, pp 671–690
Beamer WG, Donahue LR, Rosen CJ, Baylink DJ (1995) Genetic variability in adult bone density among inbred strains of mice. Bone 18: 397–403
Amling M, Herden S, Pösl M, Hahn M, Ritzel H, Delling G (1996) Heterogeneity of the skeleton: comparison of the trabecular microarchitecture of the spine, the iliac crest, the femur, and the calcaneus. J Bone Miner Res 11: 36–45
Bain SD, Bailey MC, Celino DL, Lantry MM, Edwards MW (1993) High dose estrogen inhibits bone resorption and stimulates bone formation in the ovariectomized mouse. J Bone Miner Res 8: 435- 442
Ducy P, Amling M, Takeda S, Priemel M, Schilling AS, Beil T, Shen J, Vinson C, Rueger JM, Karsenty G (2000) Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100: 197–207
Takeda T, Hosokawa M, Takeshita S, Irino M, Higuchi K, Matsushita T, Tornita Y, Yasuhira K, Hamamoto H, Shimizu K, Ishii M, Yamamuro T (1981) New murine model of accelerated senescence. Mech Ageing Dev 17: 183–194
Hosokawa M, Abe T, Higuchi K, Shimakawa K, Omori Y, Matsushita T, Kogishi K, Deguchi E, Kishimoto Y, Yasuoka K, Takeda T (1997) Management and design of the maintenance of SAM mouse strains an animal model for accelerated senescence and age-associated disorders. Exp Gerontol 32: 111–116
Matsushita M, Tsuboyama T, Kasai R, Okumura H, Yamamuro T, Higuchi K, Higuchi K, Kohno A, Yonezu T, Utani A, et al (1986) Age-related changes in bone mass in the senescence-accelerated mouse (SAM) SAM-R/3 and SAMP/6 as new murine models for senile osteoporosis. Am J Pathol 215: 276–283
Suda T (1994) Osteoporotic bone changes in SAMP6 are due to a decrease in osteoblast progenitor cells. In: Takeda T (ed) The SAM Model of Senescence. Excerpta Medica, Amsterdam, pp 47- 52
Jilka RL, Weinstein RS, Takahashi K, Parfitt AM, Manolagas SC (1996) Linkage of decreased bone mass with impaired osteoblastogenesis in murine model of accelerated senescence. J Clin Invest 97: 1732–1740
Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89: 309- 319
Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Lin Tan H, Xu W, Lacey DL, Boyle WL, Simonet WS (1998) Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12: 395–400
Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Ali E, Qian YX, Kaufman S, Sarosi I, et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93: 165- 176
Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a ligand for osteopro-tegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95: 3597–3602
Suda T, Udagawa N, Nakamura I, Miyaura C, Takahashi N (1995) Modulation of osteoclast differentiation by local factors. Bone 17: S87-S91
Nakagawa N, Kinosaki M, Yamaguchi K, et al (1999) RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun 253: 395–400
Ducy P, Starbuck M, Priemel M, Shen J, Pinero G, Geoffroy V, Amling M, Karsenty G (1999) A Cbfal-dependent genetic pathway controls bone formation beyond embryonic development. Genes Dev 13: 1025–1036
Frost HM (1979) Treatment of osteoporoses by manipulation of coherent bone cell populations. Clin Orthop 143: 227–244
Rodan GA, Martin TJ (1991) Role of osteoblasts in hormonal control of bone resorption—a hypothesis. Calcif Tissue Int 33:349- 351
Culver KW, Ram Z, Wallbridge S, Ishii H, Oldfield EH, Blaese RM (1992) In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 256: 1550–1552
Hamel W, Magnelli L, Chiarugi VP, Israel MA (1996) Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells. Cancer Res 56: 2697–2702
Corral DA, Amling M, Priemel M, Loyer E, Fuchs S, Ducy P, Baron R, Karsenty G (1998) Dissociation between bone resorption and bone formation in osteopenic transgenic mice. Proc Natl Acad Sci USA 95: 13835–13840
Amling M, Takeda S, Karsenty G (2000) A neuroendocrine regulation of bone remodeling. Bioessays 22: 970–975
Haberland M, Schilling AF, Rueger JM, Amling M (2001) Brain and bone: central regulation of bone mass. J Bone Joint Surg 83A: 1801–1809
Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G (2002) Leptin regulates bone formation via the sympathetic nervous system. Cell 111: 305–317
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Pogoda, P., Priemel, M., Schilling, A.F. et al. Mouse models in skeletal physiology and osteoporosis: experiences and data on 14839 cases from the Hamburg Mouse Archives. J Bone Miner Metab 23 (Suppl 1), 97–102 (2005). https://doi.org/10.1007/BF03026332
Issue Date:
DOI: https://doi.org/10.1007/BF03026332