Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: A novel mechanism for hormonal control of osteoblastogenesis

Teresita Bellido, A. A. Ali, I. Gubrij, Lilian Plotkin, Q. Fu, C. A. O'Brien, S. C. Manolagas, R. L. Jilka

Research output: Contribution to journalArticle

421 Citations (Scopus)

Abstract

Both chronic excess of PTH, as in hyperparathyroidism, and intermittent elevation of PTH (by daily injections) increase the number of osteoblasts; albeit, the former is associated with bone catabolism and the later with bone anabolism. Intermittent PTH increases osteoblast number by attenuating osteoblast apoptosis, an effect that requires the transcription factor Runx2. However, chronic elevation of PTH does not affect osteoblast apoptosis because it stimulates the proteasomal degradation of Runx2. Here, we studied the effects of PTH on Sost, a Runx2 target gene expressed in osteocytes (former osteoblasts embedded in the bone matrix), which antagonizes the pro-osteoblastogenic actions of bone morphogenetic proteins and Wnts. We report that continuous infusion of PTH to mice for 4 d decreased Sost mRNA expression in vertebral bone by 80-90%. This effect was accompanied by a comparable reduction of sclerostin, the product of Sost, in osteocytes, as determined by quantitative immunoblot analysis of bone extracts and by immunostaining. In contrast, a single injection of PTH caused a transient 50% reduction in Sost mRNA at 2 h, but four daily injections had no effect on Sost mRNA or sclerostin. PTH strongly decreased Sost expression in osteocytes formed in primary cultures of neonatal murine calvaria cells as well as in osteocytic MLO-A5 cells, demonstrating a direct effect of PTH on this cell type. These results, together with evidence that sclerostin antagonizes bone morphogenetic proteins and Wnts, strongly suggest that suppression of Sost by PTH represents a novel mechanism for hormonal control of osteoblastogenesis mediated by osteocytes.

Original languageEnglish (US)
Pages (from-to)4577-4583
Number of pages7
JournalEndocrinology
Volume146
Issue number11
DOIs
StatePublished - Nov 2005
Externally publishedYes

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Osteocytes
Parathyroid Hormone
Osteoblasts
Bone and Bones
Bone Morphogenetic Proteins
Messenger RNA
Injections
Apoptosis
Bone Matrix
Hyperparathyroidism
Skull
Transcription Factors
Genes

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes : A novel mechanism for hormonal control of osteoblastogenesis. / Bellido, Teresita; Ali, A. A.; Gubrij, I.; Plotkin, Lilian; Fu, Q.; O'Brien, C. A.; Manolagas, S. C.; Jilka, R. L.

In: Endocrinology, Vol. 146, No. 11, 11.2005, p. 4577-4583.

Research output: Contribution to journalArticle

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