Deletion of beta catenin in hypertrophic growth plate chondrocytes impairs trabecular bone formation

Svitlana Golovchenko, Takako Hattori, Christine Hartmann, Matthias Gebhardt, Sonja Gebhard, Andreas Hess, Friederike Pausch, Britta Schlund, Klaus Von der Mark

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

In order to elucidate the role of β-catenin in hypertrophic cartilage zone of the growth plate, we deleted the β-catenin gene ctnnb1[U+F020]specifically from hypertrophic chondrocytes by mating ctnnb1fl/fl mice with BAC-Col10a1-Cre-deleter mice. Surprisingly, this resulted in a significant reduction of subchondral trabecular bone formation in BACCol10Cre; ctnnb1δ/δ (referred to as Cat-ko) mice, although Cre expression was restricted to hypertrophic chondrocytes. The size of the Col10a1 positive hypertrophic zone was normal, but qRT-PCR revealed reduced expression of Mmp13, and Vegfa in Cat-ko hypertrophic chondrocytes, indicating impaired terminal differentiation. Immunohistological and in situ hybridization analysis revealed the substantial deficiency of collagen I positive mature osteoblasts, but equal levels of osterix-positive cells in the subchondral bone marrow space of Cat-ko mice, indicating that the supply of osteoblast precursor cells was not reduced.The fact that in Cat-ko mice subchondral trabeculae were lacking including their calcified cartilage core indicated a strongly enhanced osteoclast activity. In fact, TRAP staining as well as in situ hybridization analysis of Mmp9 expression revealed denser occupation of the cartilage erosion zone with enlarged osteoclasts as compared to the control growth plate, suggesting increased RANKL or reduced osteoprotegerin (Opg) activity in this zone. This notion was confirmed by qRT-PCR analysis of mRNA extracted from cultured hypertrophic chondrocytes or from whole epiphyses, showing increased Rankl mRNA levels in Cat-ko as compared to control chondrocytes, whereas changes in OPG levels were not significant. These results indicate that β-catenin levels in hypertrophic chondrocytes play a key role in regulating osteoclast activity and trabecular bone formation at the cartilage-bone interface by controlling RANKL expression in hypertrophic chondrocytes.

Original languageEnglish
Pages (from-to)102-112
Number of pages11
JournalBone
Volume55
Issue number1
DOIs
Publication statusPublished - Jul 2013

Keywords

  • Col10Cre
  • Endochondral ossification
  • Osteoclasts
  • Osterix
  • RANKL
  • Spongiosa

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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