Human and murine osteocalcin gene expression: Conserved tissue restricted expression and divergent responses to 1,25-dihydroxyvitamin D-3 in vivo

Sims, Natalie A., White, Christopher P., Sunn, Kate L., Thomas, Gethin P., Drummond, Melanie L., Morrison, Nigel A., Eisman, John A. and Gardiner, Edith M. (1997) Human and murine osteocalcin gene expression: Conserved tissue restricted expression and divergent responses to 1,25-dihydroxyvitamin D-3 in vivo. Molecular Endocrinology, 11 11: 1695-1708. doi:10.1210/me.11.11.1695


Author Sims, Natalie A.
White, Christopher P.
Sunn, Kate L.
Thomas, Gethin P.
Drummond, Melanie L.
Morrison, Nigel A.
Eisman, John A.
Gardiner, Edith M.
Title Human and murine osteocalcin gene expression: Conserved tissue restricted expression and divergent responses to 1,25-dihydroxyvitamin D-3 in vivo
Formatted title
Human and murine osteocalcin gene expression: Conserved tissue restricted expression and divergent responses to 1,25-dihydroxyvitamin D-3 in vivo
Journal name Molecular Endocrinology   Check publisher's open access policy
ISSN 0888-8809
1944-9917
Publication date 1997-10-01
Sub-type Article (original research)
DOI 10.1210/me.11.11.1695
Volume 11
Issue 11
Start page 1695
End page 1708
Total pages 14
Place of publication Chevy Chase, MD, United States
Publisher The Endocrine Society
Language eng
Formatted abstract
Human and murine osteocalcin genes demonstrate similar cell-specific expression patterns despite significant differences in gene locus organization and sequence variations in cis-acting regulatory elements. To investigate whether differences in these regulatory regions result in an altered response to 1,25-dihydroxyvitamin D 3 [1,25-(OH) 2D 3] in vivo, we compared the response of the endogenous mouse osteocalcin gene to a bacterial reporter gene directed by flanking regions of the human osteocalcin gene in transgenic mice. Transgene expression colocalized with endogenous osteocalcin expression in serial sections, being detected in osteoblasts, osteocytes and hypertrophic chondrocytes. In calvarial cell culture lysates from transgenic and nontransgenic mice, the endogenous mouse osteocalcin gene did not respond to 1,25-(OH) 2D 3 treatment. Despite this, transgene activity was significantly increased in the same cells. Similarly, Northern blots of total cellular RNA and in situ hybridization studies of transgenic animals demonstrated a maximal increase in transgene expression at 6 h after 1,25- (OH) 2D 3 injection (23.6 ± 3.6-fold) with a return to levels equivalent to uninjected animals by 24 h (1.2 ± 0.1-fold). This increase in transgene expression was also observed at 6 h after 1,25-(OH) 2D 3 treatment in animals on a low calcium diet (25.2 ± 7.7-fold) as well as in transgenic mice fed a vitamin D-deficient diet containing strontium chloride to block endogenous 1,25-(OH) 2D 3 production (7.5 ± 0.9-fold). In contrast to the increased transgene expression levels, neither endogenous mouse osteocalcin mRNA levels nor serum osteocalcin levels were significantly altered after 1,25-(OH) 2D 3 injection in transgenic or nontransgenic mice, regardless of dietary manipulations, supporting evidence for different mechanisms regulating the response of human and mouse osteocalcin genes to 1,25-(OH) 2D 3. Although the cis- and trans-acting mechanisms directing cell-specific gene expression appear to be conserved in the mouse and human osteocalcin genes, responsiveness to 1,25-(OH) 2D 3 is not. The mouse osteocalcin genes do not respond to 1,25-(OH) 2D 3 treatment, but the human osteocalcin-directed transgene is markedly up-regulated under the same conditions and in the same cells. The divergent responses of these homologous genes to 1,25-(OH) 2D 3 are therefore likely to be due to differences in mouse and human osteocalcin- regulatory sequences rather than to variation in the complement of trans- acting factors present in mouse osteoblastic cells. Increased understanding of these murine-human differences in osteocalcin regulation may shed light on the function of osteocalcin and its regulation by vitamin D in bone physiology.
Keyword Vitamin D receptor
Protein DNA interactions
In situ hybridization
Bone cell phenotype
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
 
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Created: Mon, 21 Mar 2011, 22:33:25 EST