Osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling bone

Jinhu Xiong, Marilina Piemontese, Melda Onal, Josh Campbell, Joseph J. Goellner, Vladimir Dusevich, Lynda Bonewald, Stavros C. Manolagas, C. A. O'Brien

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

The cytokine receptor activator of nuclear factor kappa B ligand (RANKL), encoded by the Tnfsf11 gene, is essential for osteoclastogenesis and previous studies have shown that deletion of the Tnfsf11 gene using a Dmp1-Cre transgene reduces osteoclast formation in cancellous bone by more than 70%. However, the Dmp1-Cre transgene used in those studies leads to recombination in osteocytes, osteoblasts, and lining cells making it unclear whether one or more of these cell types produce the RANKL required for osteoclast formation in cancellous bone. Because osteoblasts, osteocytes, and lining cells have distinct locations and functions, distinguishing which of these cell types are sources of RANKL is essential for understanding the orchestration of bone remodeling. To distinguish between these possibilities, we have now created transgenic mice expressing the Cre recombinase under the control of regulatory elements of the Sost gene, which is expressed in osteocytes but not osteoblasts or lining cells in murine bone. Activity of the Sost-Cre transgene in osteocytes, but not osteoblast or lining cells, was confirmed by crossing Sost-Cre transgenic mice with tdTomato and R26R Cre-reporter mice, which express tdTomato fluorescent protein or LacZ, respectively, only in cells expressing the Cre recombinase or their descendants. Deletion of the Tnfsf11 gene in Sost-Cre mice led to a threefold decrease in osteoclast number in cancellous bone and increased cancellous bone mass, mimicking the skeletal phenotype of mice in which the Tnfsf11 gene was deleted using the Dmp1-Cre transgene. These results demonstrate that osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling cancellous bone.

Original languageEnglish (US)
Article numbere0138189
JournalPLoS One
Volume10
Issue number9
DOIs
StatePublished - Sep 22 2015
Externally publishedYes

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RANK Ligand
Osteocytes
osteoclasts
osteoblasts
Bone Remodeling
Osteoblasts
Osteoclasts
Linings
Bone
bones
receptors
Genes
Transgenes
transgenes
mice
cells
gene deletion
Gene Deletion
bone formation
Transgenic Mice

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Xiong, J., Piemontese, M., Onal, M., Campbell, J., Goellner, J. J., Dusevich, V., ... O'Brien, C. A. (2015). Osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling bone. PLoS One, 10(9), [e0138189]. https://doi.org/10.1371/journal.pone.0138189

Osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling bone. / Xiong, Jinhu; Piemontese, Marilina; Onal, Melda; Campbell, Josh; Goellner, Joseph J.; Dusevich, Vladimir; Bonewald, Lynda; Manolagas, Stavros C.; O'Brien, C. A.

In: PLoS One, Vol. 10, No. 9, e0138189, 22.09.2015.

Research output: Contribution to journalArticle

Xiong, J, Piemontese, M, Onal, M, Campbell, J, Goellner, JJ, Dusevich, V, Bonewald, L, Manolagas, SC & O'Brien, CA 2015, 'Osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling bone', PLoS One, vol. 10, no. 9, e0138189. https://doi.org/10.1371/journal.pone.0138189
Xiong, Jinhu ; Piemontese, Marilina ; Onal, Melda ; Campbell, Josh ; Goellner, Joseph J. ; Dusevich, Vladimir ; Bonewald, Lynda ; Manolagas, Stavros C. ; O'Brien, C. A. / Osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling bone. In: PLoS One. 2015 ; Vol. 10, No. 9.
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