Skip to main content

Advertisement

SpringerLink
Log in

Abnormal Response to Physical Activity in Femurs after Heterozygous Inactivation of One Allele of the Col2a1 Gene for Type II Collagen in Mice

  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

The objective of this study was to evaluate the influence of heterozygous inactivation of one allele of the type II collagen gene (Col2a1) on biomechanical properties and mineral density of bone under physical loading conditions. C57BL/6−TGN mice with heterozygous knockout (HZK) inactivation of Col2a1 gene and their nontransgenic littermate controls were housed in individual cages with running wheels for 9 and 15 months. The running activity of each mouse was monitored continuously throughout the experiment. Bone mineral density (BMD) of mice femora was measured using dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computerized tomography (pQCT). Biomechanical properties were determined using three-point bending tests. Vertebral bone samples were prepared for quantitative polarized light microscopy and digital densitometry of proteoglycans. The concentration of total collagen and collagen cross-links were analyzed using high-performance liquid chromatograpy (HPLC).

The average daily running distance was shorter for the HZK mice between the age of 4 and 15 months as compared with normal runners (P < 0.05). The ultimate breaking force was 14.8% and 23.6% (9 vs. 15 months) lower in HZK-runners than in wild-type runners. BMD of the femur was 6.1% lower in HZK-runners at the age of 9 months (P < 0.05). Physical activity increased cortical BMD in wild-type runners but not in the HZK runners at the age of 9 months. The collagen network of the HZK mice was less organized. There were only minor changes in BMD and mechanical and structural properties between sedentary HZK mice and their wild-type controls. Increased physical activity induced significantly lower bone density, mechanical properties, and organization of collagen fibers in male HZK mice. However, there were no major differences in biomechanical parameters between sedentary HZK and wild-type male mice. This suggests an important guiding role of collagen type II in bone remodelling and maturation.

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.

Institutional subscriptions

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. A Aszódi A Pfeifer M Wendel L Hiripi R Fässler (1998) ArticleTitleMouse models for extracellular matrix diseases J Mol Med 76 238–252 Occurrence Handle10.1007/s001090050214 Occurrence Handle9535558

    Article  PubMed  Google Scholar 

  2. H Kuivaniemi G Tromp DJ Prockop (1991) ArticleTitleMutations in collagen genes: causes of rare and some common diseases in humans FASEB J 5 2052–2060 Occurrence Handle2010058

    PubMed  Google Scholar 

  3. BP Sokolov AN Prytkov G Tromp RG Knowlton DJ Prockop (1991) ArticleTitleExclusion of COL1A1, COL1A2, and COL3A1 genes as candidate genes for Ehlers-Danlos syndrome type I in one large family Human Genet 88 125–129 Occurrence Handle10.1007/BF00206058

    Article  Google Scholar 

  4. V Mann SH Ralston (2003) ArticleTitleMeta-analysis of COL1A1 Sp1 polymorphism in relation to bone mineral density and osteoporotic fracture Bone 32 711–717 Occurrence Handle10.1016/S8756-3282(03)00087-5 Occurrence Handle12810179

    Article  PubMed  Google Scholar 

  5. DB Kimmel WSS Jee (1982) ArticleTitleA quantitative histologic study of bone turnover in young adult beagles Anat Rec 203 31–45 Occurrence Handle10.1002/ar.1092030104 Occurrence Handle7103125

    Article  PubMed  Google Scholar 

  6. LE Lanyon (1987) ArticleTitleFunctional strain in bone tissue as an objective, and controlling stimulus for adaptive bone remodelling J Biomech 20 1083–1093 Occurrence Handle10.1016/0021-9290(87)90026-1 Occurrence Handle3323200

    Article  PubMed  Google Scholar 

  7. LE Lanyon (1992) ArticleTitleControl of bone architecture by functional load bearing J Bone Miner Res 7 IssueIDSuppl 2 S369–S375 Occurrence Handle1485545

    PubMed  Google Scholar 

  8. LE Lanyon (1993) ArticleTitleOsteocytes, strain defection, bone modeling and remodeling Calcif Tissue Int 53 IssueIDSuppl S102–107 Occurrence Handle10.1007/BF01673415 Occurrence Handle8275362

    Article  PubMed  Google Scholar 

  9. RE Burgeson ME Nimni (1992) ArticleTitleCollagen types: molecular structure and tissue distribution Clin Orthop Rel Res 282 250–272

    Google Scholar 

  10. J Bonaventure R Stanescu V Stanescu JC Allain MP Muriel D Ginisty P Maroteaux (1992) ArticleTitleType II collagen defect in two sibs with the Goldblatt syndrome, a chondrodysplasia with dentinogenesis imperfecta, and joint laxity Am J Med Genet 44 738–753 Occurrence Handle10.1002/ajmg.1320440607 Occurrence Handle1481841

    Article  PubMed  Google Scholar 

  11. M Metsäranta S Garofalo G Decker M Rintala B Crombrugghe Particlede E Vuorio (1992) ArticleTitleChondrodysplasia in transgenic mice harboring a 15-amino acid deletion in the triple helical domain of pro(alpha)1(II) collagen chain J Cell Biol 18 203–212 Occurrence Handle10.1083/jcb.118.1.203

    Article  Google Scholar 

  12. M Rintala M Metsaranta S Garofalo B Crombrugghe Particlede E Vuorio O Rönning (1993) ArticleTitleAbnormal craniofacial morphology and cartilage structure in transgenic mice harboring a Gly -> Cys mutation in the cartilage-specific type II collagen gene J Craniofac Genet Dev Biol 13 137–146 Occurrence Handle8227287

    PubMed  Google Scholar 

  13. M Rintala M Metsäranta A-M Säämänen E Vuorio O Ronning (1997) ArticleTitleAbnormal craniofacial growth and early mandibular osteoarthritis in mice harbouring a mutant type II collagen transgene J Anat 90 201–208 Occurrence Handle10.1046/j.1469-7580.1997.19020201.x

    Article  Google Scholar 

  14. KG Faulkner C-C Glüer S Majumdar P Lang K Engelke HK Genant (1991) ArticleTitleNoninvasive measurement of bone mass, structure, and strength: current methods and experimental techinques Am J Roentgenol 157 1229–1237

    Google Scholar 

  15. J Johnson B Dawson-Hughes (1991) ArticleTitlePrecision and stability of dual-energy x-ray absorptiometry measurements Calcif Tissue Int 49 174–178 Occurrence Handle1933582

    PubMed  Google Scholar 

  16. TM Keaveny WC Hayes (1993) ArticleTitleA 20-year perspective on the mechanical properties of trabecular bone J Biomech Eng 115 534–542 Occurrence Handle8302037

    PubMed  Google Scholar 

  17. H Kröger M Tuppurainen R Honkanen E Alhava S Saarikoski (1994) ArticleTitleBone mineral density and risk factors for osteoporosis—population based study of 1600 perimenopausal women Calcif Tissue Int 55 1–7 Occurrence Handle10.1007/BF00310160 Occurrence Handle7922782

    Article  PubMed  Google Scholar 

  18. KS Jensen L Mosekilde L Mosekilde (1990) ArticleTitleA model of vertebral trabecular bone architecture and its mechanical properties Bone 11 417–423 Occurrence Handle10.1016/8756-3282(90)90137-N Occurrence Handle2078435

    Article  PubMed  Google Scholar 

  19. TM Keaveny RE Borchers LJ Gibson WC Hayes (1993) ArticleTitleTrabecular bone modulus and strength can depend on specimen geometry J Biomech 26 991–1000 Occurrence Handle10.1016/0021-9290(93)90059-N Occurrence Handle8349722

    Article  PubMed  Google Scholar 

  20. T Jämsä A Koivukangas J Ryhänen P Jalovaara J Tuukkanen (1999) ArticleTitleFemoral neck is a sensitive indicator of bone loss in immobilized hind limb of mouse J Bone Miner Res 14 1708–1713 Occurrence Handle10491218

    PubMed  Google Scholar 

  21. T Jämsä P Jalovaara Z Peng HK Väänänen J Tuukkanen (1998) ArticleTitleComparison of three-point bending test and pQCT analysis in the evaluation of the strength of mouse femur and tibia Bone 23 155–161 Occurrence Handle10.1016/S8756-3282(98)00076-3 Occurrence Handle9701475

    Article  PubMed  Google Scholar 

  22. S-W Li DJ Prockop H Helminen R Fässler T Lapveteläinen K Kiraly A Pelttari J Arokoski H Lui M Arita JS Khillan (1995) ArticleTitleTransgenic mice with targeted inactivation of the Col2 alpha 1 gene for collagen II develop a skeleton with membranous and periosteal bone but no endochondral bone Gene Dev 9 2821–2830 Occurrence Handle7590256

    PubMed  Google Scholar 

  23. M Vikkula A Palotie P Ritvaniemi J Ott L Ala-Kokko U Sievers K Aho L Peltonen (1993) ArticleTitleEarly-onset osteoarthritis linked to the type II procollagen gene Arthritis & Rheum 36 401–409

    Google Scholar 

  24. DE Busier S-W Li (1996) ArticleTitleRapid screening of transgenic type II and type XI collagen knock-out mice with three-primer PCR Biotechniques 21 1002–1004 Occurrence Handle8969822

    PubMed  Google Scholar 

  25. T Lapveteläinen A Tiihonen P Koskela T Nevalainen J Lindblom K Kiraly P Halonen HJ Helminen (1997) ArticleTitleTraining a large number of laboratory mice using running wheels and analyzing running behavior by use of a computer-assisted system Lab Anim Sci 47 172–179 Occurrence Handle9150497

    PubMed  Google Scholar 

  26. T Jämsä P Jalovaara Z Peng K Väänänen (1996) ArticleTitleEquipment for testing the biomechanical strength oibones Med Biol Eng Comput 34 IssueIDSuppl 1, P 1 347–348

    Google Scholar 

  27. JPA Arokoski MM Hyttinen T Lapveteläinen P Takács B Kosztáczky L Módis V Kovanen HJ Helminen (1996) ArticleTitleDecreased birefringence of the superficial zone collagen network in the canine knee (stifle) articular cartilage after long distance running training, detected by quantitative polarised light microscopy Ann Rheum Dis 55 253–264 Occurrence Handle8733443

    PubMed  Google Scholar 

  28. K Király MM Hyttinen T Lapveteläinen M Elo I Kiviranta J Dobai L Módis HJ Helminen JPA Arokoski (1997) ArticleTitleSpecimen preparation and quantification of collagen birefringence in unstained sections of articular cartilage using image analysis and polarizing light microscopy Histochem J 29 317–327 Occurrence Handle10.1023/A:1020802631968 Occurrence Handle9184847

    Article  PubMed  Google Scholar 

  29. K Király T Lapveteläinen J Arokoski K Törrönen L Módis I Kiviranta HJ Helminen (1996) ArticleTitleApplication of selected cationic dyes for the semiquantitative estimation of glycosaminoglycans in histological sections of articular cartilage by microspectrophotometry Histochem J 28 577–590 Occurrence Handle8894661

    PubMed  Google Scholar 

  30. K Puustjärvi J Nieminen T Räsänen M Hyttinen HJ Helminen H Kröger J Huuskonen E Alhava V Kovanen (1999) ArticleTitleDo more highly organized collagen fibrils increase bone mechanical strength in loss of mineral density after one-year running training? J Bone Miner Res 14 321–329 Occurrence Handle10027896

    PubMed  Google Scholar 

  31. J Sahlman R Inkinen T Hirvonen MJ Lammi PE Lammi J Nieminen T Lapveteläinen DJ Prockop M Arita S-W Li MM Hyttinen HJ Helminen K Puustjärvi (2001) ArticleTitlePremature vertebral endplate ossification and mild disc degeneration in mice after inactivation of one allele belonging to the col2a1 gene for type II collagen Spine 26 2558–2565 Occurrence Handle10.1097/00007632-200112010-00008 Occurrence Handle11725236

    Article  PubMed  Google Scholar 

  32. CM Riggs LC Vaughan GP Evans LE Lanyon A Boyde (1993) ArticleTitleMechanical implications of collagen fibre orientation in cortical bone of the equine radius Anat Embryol 187 239–248 Occurrence Handle8470824

    PubMed  Google Scholar 

  33. AJ Bailey TJ Sims EN Ebbesen JP Mansell JS Thomsen L Mosekilde (1999) ArticleTitleAge-related changes in the biochemical properties of human cancellous bone collagen: relationship to bone strength Calcif Tissue Int 65 203–210 Occurrence Handle10.1007/s002239900683 Occurrence Handle10441651

    Article  PubMed  Google Scholar 

  34. NK Arden J Baker C Hogg K Baan TD Spector (1996) ArticleTitleThe heritability of bone mineral density, ultrasound of thecalcaneus and hip axis length: a study of postmenopausal twins J Bone Miner Res 11 530–534 Occurrence Handle8992884

    PubMed  Google Scholar 

  35. RB Martin DL Boardman (1993) ArticleTitleThe effect of collagen fiber orientation, porosity, density, and mineralization on bovine cortical bone bending properties J Biomech 26 1047–1054 Occurrence Handle8408087

    PubMed  Google Scholar 

  36. TM Skerry L Bitensky J Chayen LE Lanyon (1988) ArticleTitleLoading-related reorientation of bone proteoglycan in vivo. Strain memory in bone tissue? J Orthop Res 6 547–551 Occurrence Handle10.1002/jor.1100060411 Occurrence Handle3379508

    Article  PubMed  Google Scholar 

  37. MM Hyttinen J Töyräs T Lapveteläinen J Lindblom DJ Prockop S-W Li M Arita JS Jurvelin HJ Helminen (2001) ArticleTitleInactivation of one allele of the type II collagen gene alters the collagen network in murine articular cartilage and makes cartilage softer Annals of the Rheumatic Diseases 60 262–268 Occurrence Handle10.1136/ard.60.3.262 Occurrence Handle11171689

    Article  PubMed  Google Scholar 

  38. L Sokoloff (1956) ArticleTitleNatural history of degenerativejpint disease in small laboratory animals Arch Pathol 62 118–128

    Google Scholar 

  39. M Harri J Lindblom H Malinen (1999) ArticleTitleEffect of access to a running wheel on behavior of C57BL/6 J mice Lab Anim Sci 49 401–405 Occurrence Handle10480645

    PubMed  Google Scholar 

  40. KR Gordon P Burns G Keller (1992) ArticleTitleExperimental changes in mineral content of juvenile mouse femora Calcif Tissue Int 51 229–232 Occurrence Handle10.1007/BF00334552 Occurrence Handle1422967

    Article  PubMed  Google Scholar 

  41. KR Gordon M Perl C Levy (1989) ArticleTitleStructural alterations and breaking strength of mouse femora exposed to three activity regimens Bone 10 303–312 Occurrence Handle10.1016/8756-3282(89)90068-9 Occurrence Handle2803867

    Article  PubMed  Google Scholar 

  42. BL Drinkwater K Nilson CH Chesnut SuffixIII WJ Bremer S Shainholtz MB Southworth (1984) ArticleTitleBone mineral content of amenorrheic and eumenorrheic athletes N Engl J Med 311 277–281 Occurrence Handle6738640

    PubMed  Google Scholar 

  43. K-F Tseng SA Goldstein (1998) ArticleTitleSystemic over-secretion of growth hormone in transgenic mice results in a specific pattern of skeletal modeling and adaptation J Bone Miner Res 13 706–715 Occurrence Handle9556071

    PubMed  Google Scholar 

  44. DJ McBride SuffixJr. JR Shapiro MG Dunn (1998) ArticleTitleBone geometry and strength measurements in aging mice with the oim mutation Calcif Tissue Int 62 172–176 Occurrence Handle10.1007/s002239900412 Occurrence Handle9437052

    Article  PubMed  Google Scholar 

  45. HJ Helminen K Kiraly A Pelttari Tammi Ml P Vandenberg R Pereira R Dhulipata JS Khillan L Ala-Kokko EL Hume BP Sokolov DJ Prockop (1993) ArticleTitleAn inbred line of transgenic mice expressing an internally deleted gene for type II procollagen (COL2A1) J Clin Invest 92 582–595 Occurrence Handle8349798

    PubMed  Google Scholar 

  46. M Savontaus M Metsäranta E Vuorio (1996) ArticleTitleRetarded skeletal development in transgenic mice with a type II collagen mutation Am J Pathol 149 2169–2182 Occurrence Handle8952549

    PubMed  Google Scholar 

  47. TLN Järvinen H Sievänen P Kannus M Järvinen (1998) ArticleTitleDual-energy x-ray absorptiometry in predicting mechanical characteristics of rat femur Bone 22 555–558

    Google Scholar 

  48. K Puustjärvi P Karjalainen J Nieminen HJ Helminen S Soimakallio T Kivimäki J Arokoski (1991) ArticleTitleEffect of long-term running on spinal mineral content in dogs Calcif Tissue Int 49 IssueIDSuppl S81–S82 Occurrence Handle1933610

    PubMed  Google Scholar 

  49. K Puustjärvi P Karjalainen J Nieminen J Arokoski M Parviainen HJ Helminen S Soimakallio (1992) ArticleTitleEndurance training associated with slightly lowered serum estradiol levels decreases mineral density of canine skeleton J Bone Miner Res 7 619–624 Occurrence Handle1414479

    PubMed  Google Scholar 

  50. K Puustjärvi R Lappalainen L Niemitukia I Arnala J Nieminen M Tammi HJ Helminen (1995) ArticleTitleLong-distance running alters bone anthropometry, elemental composition and mineral density of young dogs Scand J Med Sci Sports 5 17–23 Occurrence Handle7882122

    PubMed  Google Scholar 

  51. EM Alhava (1991) ArticleTitleBone density measurements Calcif Tissue Int 49 IssueIDSuppl S21–S23 Occurrence Handle1933591

    PubMed  Google Scholar 

  52. WG Beamer LR Donahue CJ Rosen DJ Raylink (1996) ArticleTitleGenetic variability in adult bone density among inbred strains of mice Bone 18 397–403 Occurrence Handle10.1016/8756-3282(96)00047-6 Occurrence Handle8739896

    Article  PubMed  Google Scholar 

  53. X Li W Gu G Masinde M Hamilton-Ulland CH Rundle S Mohan DJ Baylink (2001) ArticleTitleGenetic variation in bone-regenerative capacity among inbred strains of mice Bone 29 134–140 Occurrence Handle10.1016/S8756-3282(01)00497-5 Occurrence Handle11502474

    Article  PubMed  Google Scholar 

  54. TLN Järvinen P Kannus I Pajamäki T Vuohelainen J Tuukkanen M Järvinen H Sievänen (2003) ArticleTitleEstrogen deposits extra mineral into bones of female rats in puberty, but simultaneously seems to suppress the responsiveness of female skeleton to mechanical loading Bone 32 642–651 Occurrence Handle10.1016/S8756-3282(03)00100-5 Occurrence Handle12810171

    Article  PubMed  Google Scholar 

  55. TLN Järvinen P Kannus H Sievänen (2003) ArticleTitleEstrogen and bone - a reproductive and locomotive perspective J Bone Miner Res 18 1921–1931 Occurrence Handle14606503

    PubMed  Google Scholar 

  56. L Wang CA McMahan J Banu MC Okafor (2003) ArticleTitleRodent model for investigating the effects of estrogen on bone and muscle relationship during growth Calcif Tissue Int 72 151–155 Occurrence Handle10.1007/s00223-001-1122-y Occurrence Handle12469248

    Article  PubMed  Google Scholar 

  57. RW McCalden JA McGeough MB Barker CM Court-Brown (1993) ArticleTitleAge-related changes in the tensile properties of cortical bone J Bone Joint Surg Am 75 1193–1205 Occurrence Handle8354678

    PubMed  Google Scholar 

  58. TJ Beck CB Ruff K Bissessur (1993) ArticleTitleAge-related changes in female femoral neck geometry: implications for bone strenght Calcif Tissue Int 53 IssueIDSuppl S41–S46 Occurrence Handle10.1007/BF01673401 Occurrence Handle8275379

    Article  PubMed  Google Scholar 

  59. GP Stickler (1965) ArticleTitleHereditary progressive arthroophtalmopathy Mayo Clin Proc 40 547–551

    Google Scholar 

  60. JI Sebes S Kasthuri (2000) ArticleTitleHereditary arthro-opthalmopathy (Stickler sndrome Skeletal Radiol 29 613–616 Occurrence Handle10.1007/s002560000268 Occurrence Handle11127688

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anatomy, University of Kuopio, P.O.B. 1627, FIN-70211 Kuopio, Finland

    J. Sahlman, T. Hirvonen, M. M. Hyttinen, H. J. Helminen & T. Lapveteläinen

  2. Department of Medical Technology, University of Oulu, P.O.B. 3000, FIN-90014 Oulu, Finland

    T. Jämsä

  3. Department of Anatomy and Cell Biology, University of Oulu, P.O.B. 3000, FIN-90014 Oulu, Finland

    J. Tuukkanen

  4. Department of Health Sciences, University of Jyväskylä, P.O.B. 35, FIN-40014 Jyväskylä, Finland

    V. Kovanen

  5. Department of Surgery, University Hospital of Kuopio, P.O.B. 1777, FIN-70211 Kuopio, Finland

    H. Kröger

  6. Department of Clinical Physiology, University Hospital of Kuopio, P.O.B. 1777, FIN-70211 Kuopio, Finland

    J. Jurvelin

  7. Department of Surgery, University Hospital of Tampere and Coxa Hospital for Joint Replacement, P.O.B. 652, FIN-33101, Tampere, Finland

    J. Nieminen

  8. Center for Gene Therapy, MCP Hahnemann University, 245 N 15th St., Philadelphia, PA 19102-1192, USA

    M. Arita, S. W. Li & D.J. Prockop

  9. Department of Physical Medicine and Rehabilitation, University Hospital of Helsinki, P.O.B. 263, FIN-00029 HUS, Finland

    K. Puustjärvi

Authors
  1. J. Nieminen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Sahlman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. Hirvonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T. Jämsä
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. Tuukkanen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. V. Kovanen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H. Kröger
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J. Jurvelin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. Arita
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S. W. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. D.J. Prockop
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M. M. Hyttinen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. H. J. Helminen
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. T. Lapveteläinen
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. K. Puustjärvi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Nieminen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nieminen, J., Sahlman, J., Hirvonen, T. et al. Abnormal Response to Physical Activity in Femurs after Heterozygous Inactivation of One Allele of the Col2a1 Gene for Type II Collagen in Mice. Calcif Tissue Int 77, 104–112 (2005). https://doi.org/10.1007/s00223-004-0069-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-004-0069-1

Keywords

Search

Navigation