Calcified Tissue International

, Volume 76, Issue 1, pp 39–49 | Cite as

Skeletal Phenotype of Growing Transgenic Mice that Express a Function-Perturbing Form of β1 Integrin in Osteoblasts

  • R. K. Globus
  • D. Amblard
  • Y. Nishimura
  • U. T. Iwaniec
  • J.-B. Kim
  • E. A. C. Almeida
  • C. D. Damsky
  • T. J. Wronski
  • M. C. H. van der Meulen
Article

Abstract

Skeletal modeling entails the deposition of large amounts of extracellular matrix (ECM) to form structures tailored to withstand increasing mechanical loads during rapid growth. Specific ECM molecules bind to integrin receptors on the cell surface, thereby triggering a cascade of signaling events that affect critical cell functions. To evaluate the role of integrins during skeletal growth, transgenic mice were engineered to express a function-perturbing fragment of β1 integrin consisting of the transmembrane domain and cytoplasmic tail under the control of the osteocalcin promoter (TG mice). Thus, transgene expression was targeted to mature cells of the osteoblast lineage, and herein we show that cultured cells resembling osteocytes from 90-day-old TG mice display impaired adhesion to collagen I, a ligand for β1 integrin. To determine the influence of β1 integrin on bones that are responsible for providing structural support during periods of rapid growth, we examined the phenotype of the appendicular skeleton in TG mice compared to wild type (WT) mice. According to radiographs, bones from mice of both genotypes between 14 and 90 days of age appeared similar in gross structure and density, although proximal tibiae from 35–90 days old TG mice were less curved than those of WT mice (72–92% TG/WT). Although there were only mild and transient differences in absolute bone mass and strength, once normalized to body mass, the tibial dry mass (79.1% TG/WT females), ash mass (78.5% TG/WT females), and femoral strength in torsion (71.6% TG/WT females) were reduced in TG mice compared to WT mice at 90 days of age. Similar effects of genotype on bone mass and curvature were observed in 1-year-old retired breeders, indicating that these phenotypic differences between TG and WT mice were stable well into adulthood. Effects of genotype on histomorphometric indices of cancellous bone turnover were minimal and evident only transiently during growth, but when present they demonstrated differences in osteoblast rather than osteoclast parameters. Together, these results suggest that integrin signals generated during growth enhance the acquisition of a skeletal mass, structure, and strength to withstand the mechanical loads generated by weight-bearing.

Notes

Acknowledgments

We thank Dr. Randall Kramer (UCSF) for the kind gift of β1 integrin antibodies. We are also grateful to Emily Morey-Holton for helpful discussions and critical reading of the manuscript. We thank Veronica Rocha and Julie Litzenberger for technical assistance at NASA Ames Research Center, Nathan Netravali for torsion tests and Heather Ansorge for bending tests at Cornell University, Neda Mitova-Caneva for technical assistance at the University of Florida, and Dr. Patricia Calarco and Mercedes Joaquin for assistance with the transgenic colony at UCSF. This research was supported by NASA grant #99-HEDS-062 and NIH grant #P60 DE13058.

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • R. K. Globus
    • 1
    • 2
  • D. Amblard
    • 1
    • 2
  • Y. Nishimura
    • 1
    • 2
  • U. T. Iwaniec
    • 3
  • J.-B. Kim
    • 2
  • E. A. C. Almeida
    • 1
    • 2
  • C. D. Damsky
    • 2
  • T. J. Wronski
    • 3
  • M. C. H. van der Meulen
    • 4
  1. 1.Life Sciences DivisionNASA Ames Research CenterMoffett FieldUSA
  2. 2.Department of StomatologyUniversity of CaliforniaSan FranciscoUSA
  3. 3.Department of Physiological SciencesUniversity of FloridaGainesvilleUSA
  4. 4.Sibley School of Mechanical and Aerospace EngineeringCornell UniversityIthacaUSA

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