Pro416Arg cherubism mutation in Sh3bp2 knock-in mice affects osteoblasts and alters bone mineral and matrix properties

Chiachien J. Wang, I. Ping Chen, Boguslawa Koczon-Jaremko, Adele L. Boskey, Yasuyoshi Ueki, Liisa Kuhn, Ernst J. Reichenberger

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Cherubism is an autosomal dominant disorder in children characterized by unwarranted symmetrical bone resorption of the jaws with fibrous tissue deposition. Mutations causing cherubism have been identified in the adaptor protein SH3BP2. Knock-in mice with a Pro416Arg mutation in Sh3bp2 exhibit a generalized osteoporotic bone phenotype. In this study, we examined the effects of this "cherubism" mutation on spectroscopic indices of "bone quality" and on osteoblast differentiation. Fourier-transform infrared imaging (FTIRI) analysis of femurs from wild-type and Sh3bp2 knock-in mice showed decreased mineral content, decreased mineral crystallinity/crystal size, and increased collagen maturity in homozygous mutants. To assess osteoblast maturation in vivo, knock-in mice were crossed with transgenic mice over-expressing GFP driven by 3.6-kb or 2.3-kb Col1a1 promoter fragments. Reduced numbers of mature osteoblasts were observed in homozygous mice. Neonatal calvarial cultures, which were enriched for osteoblasts by depletion of hematopoietic cells (negative selection for Ter119- and CD45-positive cells) were investigated for osteoblast-specific gene expression and differentiation, which demonstrated that differentiation and mineralization in homozygous osteoblast cultures was impaired. Co-cultures with calvarial osteoblasts and bone marrow macrophages showed that mutant osteoblasts appear to increase osteoclastogenesis resulting in increased bone resorption on bone chips. In summary, the Sh3bp2 mutation in cherubism mice alters bone quality, reduces osteoblast function, and may contribute to excessive bone resorption by osteoclasts. Our data, together with previous osteoclast studies, demonstrate a critical role of Sh3bp2 in bone remodeling and osteoblast differentiation.

Original languageEnglish (US)
Pages (from-to)1306-1315
Number of pages10
JournalBone
Volume46
Issue number5
DOIs
StatePublished - May 1 2010
Externally publishedYes

Fingerprint

Cherubism
Bone Matrix
Osteoblasts
Minerals
Mutation
Bone Resorption
Bone and Bones
Osteoclasts
Bone Remodeling
Fourier Analysis
Coculture Techniques
Jaw
Osteogenesis
Femur
Transgenic Mice

Keywords

  • Cherubism
  • Fourier-transform infrared imaging
  • GFP transgenic mice
  • Osteoblast
  • Sh3bp2

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

Cite this

Wang, C. J., Chen, I. P., Koczon-Jaremko, B., Boskey, A. L., Ueki, Y., Kuhn, L., & Reichenberger, E. J. (2010). Pro416Arg cherubism mutation in Sh3bp2 knock-in mice affects osteoblasts and alters bone mineral and matrix properties. Bone, 46(5), 1306-1315. https://doi.org/10.1016/j.bone.2010.01.380

Pro416Arg cherubism mutation in Sh3bp2 knock-in mice affects osteoblasts and alters bone mineral and matrix properties. / Wang, Chiachien J.; Chen, I. Ping; Koczon-Jaremko, Boguslawa; Boskey, Adele L.; Ueki, Yasuyoshi; Kuhn, Liisa; Reichenberger, Ernst J.

In: Bone, Vol. 46, No. 5, 01.05.2010, p. 1306-1315.

Research output: Contribution to journalArticle

Wang, CJ, Chen, IP, Koczon-Jaremko, B, Boskey, AL, Ueki, Y, Kuhn, L & Reichenberger, EJ 2010, 'Pro416Arg cherubism mutation in Sh3bp2 knock-in mice affects osteoblasts and alters bone mineral and matrix properties', Bone, vol. 46, no. 5, pp. 1306-1315. https://doi.org/10.1016/j.bone.2010.01.380
Wang, Chiachien J. ; Chen, I. Ping ; Koczon-Jaremko, Boguslawa ; Boskey, Adele L. ; Ueki, Yasuyoshi ; Kuhn, Liisa ; Reichenberger, Ernst J. / Pro416Arg cherubism mutation in Sh3bp2 knock-in mice affects osteoblasts and alters bone mineral and matrix properties. In: Bone. 2010 ; Vol. 46, No. 5. pp. 1306-1315.
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AU - Boskey, Adele L.

AU - Ueki, Yasuyoshi

AU - Kuhn, Liisa

AU - Reichenberger, Ernst J.

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AB - Cherubism is an autosomal dominant disorder in children characterized by unwarranted symmetrical bone resorption of the jaws with fibrous tissue deposition. Mutations causing cherubism have been identified in the adaptor protein SH3BP2. Knock-in mice with a Pro416Arg mutation in Sh3bp2 exhibit a generalized osteoporotic bone phenotype. In this study, we examined the effects of this "cherubism" mutation on spectroscopic indices of "bone quality" and on osteoblast differentiation. Fourier-transform infrared imaging (FTIRI) analysis of femurs from wild-type and Sh3bp2 knock-in mice showed decreased mineral content, decreased mineral crystallinity/crystal size, and increased collagen maturity in homozygous mutants. To assess osteoblast maturation in vivo, knock-in mice were crossed with transgenic mice over-expressing GFP driven by 3.6-kb or 2.3-kb Col1a1 promoter fragments. Reduced numbers of mature osteoblasts were observed in homozygous mice. Neonatal calvarial cultures, which were enriched for osteoblasts by depletion of hematopoietic cells (negative selection for Ter119- and CD45-positive cells) were investigated for osteoblast-specific gene expression and differentiation, which demonstrated that differentiation and mineralization in homozygous osteoblast cultures was impaired. Co-cultures with calvarial osteoblasts and bone marrow macrophages showed that mutant osteoblasts appear to increase osteoclastogenesis resulting in increased bone resorption on bone chips. In summary, the Sh3bp2 mutation in cherubism mice alters bone quality, reduces osteoblast function, and may contribute to excessive bone resorption by osteoclasts. Our data, together with previous osteoclast studies, demonstrate a critical role of Sh3bp2 in bone remodeling and osteoblast differentiation.

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