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The class II histone deacetylase HDAC4 regulates cognitive, metabolic and endocrine functions through its expression in osteoblasts.

Makinistoglu MP, Karsenty G - Mol Metab (2014)

Bottom Line: In contrast, the role of chromatin remodeling enzymes, such as histone deacetylases (HDACs), in this process has not as yet been thoroughly understood.Remarkably, through its expression in osteoblasts, HDAC4 also enhances appetite, a physiological function that is not regulated by osteocalcin.These results provide a more in depth molecular understanding of the regulation of the endocrine functions of the osteoblast, and suggest the existence of additional hormones synthesized by osteoblasts that also regulate appetite.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Development, Columbia University, New York, NY 10032, USA.

ABSTRACT

Objective: The recently described endocrine functions of osteoblasts raise questions about their transcriptional regulation. Thus far, this aspect of osteoblast biology has been addressed only by examining the role of transcription factors binding to specific cis-acting elements in the promoter of the Osteocalcin gene.

Methods: In contrast, the role of chromatin remodeling enzymes, such as histone deacetylases (HDACs), in this process has not as yet been thoroughly understood.

Results: Here we show that through its expression in osteoblasts, one class II HDAC molecule, HDAC4, favors Osteocalcin expression, and as a result, the physiological functions regulated by osteocalcin such as spatial learning, memory, male fertility and insulin secretion. Molecular and genetic evidence indicates that through its expression in osteoblasts HDAC4 fulfills these long-range functions in part by stabilizing the transcription factor ATF4. Remarkably, through its expression in osteoblasts, HDAC4 also enhances appetite, a physiological function that is not regulated by osteocalcin.

Conclusions: These results provide a more in depth molecular understanding of the regulation of the endocrine functions of the osteoblast, and suggest the existence of additional hormones synthesized by osteoblasts that also regulate appetite.

No MeSH data available.


Related in: MedlinePlus

(A) Analysis of Osteocalcin expression in 2-month-old Hdac4f/f (n = 11), Hdac4osb−/−(n = 11) bones. Results are presented as fold changes compared to levels seen in bones of Hdac4f/f or WT mice. (B) Analysis of Osteocalcin expression in 2-month-old control (n = 8), Atf4osb+/− (n = 2), Hdac4osb+/− (n = 3), Atf4osb+/−;Hdac4osb+/− (n = 4) bones. Results are presented as fold changes compared to levels seen in bones of control mice. (C) Analysis of Atf4 and Hdac4 expression in 2-month-old control (n = 8), Atf4osb+/− (n = 2), Hdac4osb+/− (n = 3), Atf4osb+/−;Hdac4osb+/− (n = 4) bones. Results are presented as fold changes compared to levels seen in bones of Hdac4f/f or control mice. (D) Circulating levels of total and undercarboxylated osteocalcin in Hdac4f/f (n = 11), Hdac4osb−/− (n = 11), control (n = 8), Atf4osb+/− (n = 2), Hdac4osb+/− (n = 3), Atf4osb+/−;Hdac4osb+/− (n = 4) mice. Results are given as means ± SEM. *p < 0.05 by Student's t-test.
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fig1: (A) Analysis of Osteocalcin expression in 2-month-old Hdac4f/f (n = 11), Hdac4osb−/−(n = 11) bones. Results are presented as fold changes compared to levels seen in bones of Hdac4f/f or WT mice. (B) Analysis of Osteocalcin expression in 2-month-old control (n = 8), Atf4osb+/− (n = 2), Hdac4osb+/− (n = 3), Atf4osb+/−;Hdac4osb+/− (n = 4) bones. Results are presented as fold changes compared to levels seen in bones of control mice. (C) Analysis of Atf4 and Hdac4 expression in 2-month-old control (n = 8), Atf4osb+/− (n = 2), Hdac4osb+/− (n = 3), Atf4osb+/−;Hdac4osb+/− (n = 4) bones. Results are presented as fold changes compared to levels seen in bones of Hdac4f/f or control mice. (D) Circulating levels of total and undercarboxylated osteocalcin in Hdac4f/f (n = 11), Hdac4osb−/− (n = 11), control (n = 8), Atf4osb+/− (n = 2), Hdac4osb+/− (n = 3), Atf4osb+/−;Hdac4osb+/− (n = 4) mice. Results are given as means ± SEM. *p < 0.05 by Student's t-test.

Mentions: As a first approach to determine if HDAC4 could affect some of the long-range functions exerted by the osteoblast, we measured Osteocalcin expression in mice lacking Hdac4 only in osteoblasts (Hdac4osb−/−). As shown in Figure 1A, Osteocalcin expression in bone was decreased nearly 4-fold in Hdac4osb−/− compared with control mice and more moderately, and not significantly, in Hdac4osb+/- mice (Figure 1A,B). This regulation of Osteocalcin expression by class II HDACs appeared to be specific to HDAC4, as mice lacking another class II HDAC, HDAC5, did not experience any decrease in Osteocalcin expression (Figure 1A). To determine if HDAC4 regulates Osteocalcin expression in part through its association with ATF4 [22], we generated compound heterozygous mice lacking one copy of Hdac4 and one copy of Atf4 in osteoblasts only. As shown previously, this gene deletion strategy removed Hdac4 and Atf4 from osteoblasts but not from any other tissues tested (Figure 1C) [13,22]. Osteocalcin expression was significantly decreased in Atf4osb+/−; Hdac4osb+/− mice although not to the same extent as in Hdac4osb−/− mice (Figure 1B). This latter observation suggests that HDAC4 may interact with additional transcription factors besides ATF4 to regulate Osteocalcin expression. Nevertheless, in agreement with this decrease in Osteocalcin expression, the circulating level of all forms of osteocalcin, including its undercarboxylated i.e., active, form were decreased in a statistically significant manner in Hdac4osb−/− and Atf4osb+/−;Hdac4osb+/− but not in Hdac4osb+/− or Atf4osb+/− mice when compared with control mice (Figure 1D). These data indicate that HDAC4 is a regulator of Osteocalcin expression in part because it enhances the activity of ATF4 in osteoblasts. This regulation of Osteocalcin expression by HDAC4-ATF4 complex appears to be independent of the regulation of HDAC4 activity by the sympathetic nervous system, since Atf4 expression is normal in Adrb2osb−/− mice (data not shown) and isoproterenol does not regulate Osteocalcin expression [24].


The class II histone deacetylase HDAC4 regulates cognitive, metabolic and endocrine functions through its expression in osteoblasts.

Makinistoglu MP, Karsenty G - Mol Metab (2014)

(A) Analysis of Osteocalcin expression in 2-month-old Hdac4f/f (n = 11), Hdac4osb−/−(n = 11) bones. Results are presented as fold changes compared to levels seen in bones of Hdac4f/f or WT mice. (B) Analysis of Osteocalcin expression in 2-month-old control (n = 8), Atf4osb+/− (n = 2), Hdac4osb+/− (n = 3), Atf4osb+/−;Hdac4osb+/− (n = 4) bones. Results are presented as fold changes compared to levels seen in bones of control mice. (C) Analysis of Atf4 and Hdac4 expression in 2-month-old control (n = 8), Atf4osb+/− (n = 2), Hdac4osb+/− (n = 3), Atf4osb+/−;Hdac4osb+/− (n = 4) bones. Results are presented as fold changes compared to levels seen in bones of Hdac4f/f or control mice. (D) Circulating levels of total and undercarboxylated osteocalcin in Hdac4f/f (n = 11), Hdac4osb−/− (n = 11), control (n = 8), Atf4osb+/− (n = 2), Hdac4osb+/− (n = 3), Atf4osb+/−;Hdac4osb+/− (n = 4) mice. Results are given as means ± SEM. *p < 0.05 by Student's t-test.
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fig1: (A) Analysis of Osteocalcin expression in 2-month-old Hdac4f/f (n = 11), Hdac4osb−/−(n = 11) bones. Results are presented as fold changes compared to levels seen in bones of Hdac4f/f or WT mice. (B) Analysis of Osteocalcin expression in 2-month-old control (n = 8), Atf4osb+/− (n = 2), Hdac4osb+/− (n = 3), Atf4osb+/−;Hdac4osb+/− (n = 4) bones. Results are presented as fold changes compared to levels seen in bones of control mice. (C) Analysis of Atf4 and Hdac4 expression in 2-month-old control (n = 8), Atf4osb+/− (n = 2), Hdac4osb+/− (n = 3), Atf4osb+/−;Hdac4osb+/− (n = 4) bones. Results are presented as fold changes compared to levels seen in bones of Hdac4f/f or control mice. (D) Circulating levels of total and undercarboxylated osteocalcin in Hdac4f/f (n = 11), Hdac4osb−/− (n = 11), control (n = 8), Atf4osb+/− (n = 2), Hdac4osb+/− (n = 3), Atf4osb+/−;Hdac4osb+/− (n = 4) mice. Results are given as means ± SEM. *p < 0.05 by Student's t-test.
Mentions: As a first approach to determine if HDAC4 could affect some of the long-range functions exerted by the osteoblast, we measured Osteocalcin expression in mice lacking Hdac4 only in osteoblasts (Hdac4osb−/−). As shown in Figure 1A, Osteocalcin expression in bone was decreased nearly 4-fold in Hdac4osb−/− compared with control mice and more moderately, and not significantly, in Hdac4osb+/- mice (Figure 1A,B). This regulation of Osteocalcin expression by class II HDACs appeared to be specific to HDAC4, as mice lacking another class II HDAC, HDAC5, did not experience any decrease in Osteocalcin expression (Figure 1A). To determine if HDAC4 regulates Osteocalcin expression in part through its association with ATF4 [22], we generated compound heterozygous mice lacking one copy of Hdac4 and one copy of Atf4 in osteoblasts only. As shown previously, this gene deletion strategy removed Hdac4 and Atf4 from osteoblasts but not from any other tissues tested (Figure 1C) [13,22]. Osteocalcin expression was significantly decreased in Atf4osb+/−; Hdac4osb+/− mice although not to the same extent as in Hdac4osb−/− mice (Figure 1B). This latter observation suggests that HDAC4 may interact with additional transcription factors besides ATF4 to regulate Osteocalcin expression. Nevertheless, in agreement with this decrease in Osteocalcin expression, the circulating level of all forms of osteocalcin, including its undercarboxylated i.e., active, form were decreased in a statistically significant manner in Hdac4osb−/− and Atf4osb+/−;Hdac4osb+/− but not in Hdac4osb+/− or Atf4osb+/− mice when compared with control mice (Figure 1D). These data indicate that HDAC4 is a regulator of Osteocalcin expression in part because it enhances the activity of ATF4 in osteoblasts. This regulation of Osteocalcin expression by HDAC4-ATF4 complex appears to be independent of the regulation of HDAC4 activity by the sympathetic nervous system, since Atf4 expression is normal in Adrb2osb−/− mice (data not shown) and isoproterenol does not regulate Osteocalcin expression [24].

Bottom Line: In contrast, the role of chromatin remodeling enzymes, such as histone deacetylases (HDACs), in this process has not as yet been thoroughly understood.Remarkably, through its expression in osteoblasts, HDAC4 also enhances appetite, a physiological function that is not regulated by osteocalcin.These results provide a more in depth molecular understanding of the regulation of the endocrine functions of the osteoblast, and suggest the existence of additional hormones synthesized by osteoblasts that also regulate appetite.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Development, Columbia University, New York, NY 10032, USA.

ABSTRACT

Objective: The recently described endocrine functions of osteoblasts raise questions about their transcriptional regulation. Thus far, this aspect of osteoblast biology has been addressed only by examining the role of transcription factors binding to specific cis-acting elements in the promoter of the Osteocalcin gene.

Methods: In contrast, the role of chromatin remodeling enzymes, such as histone deacetylases (HDACs), in this process has not as yet been thoroughly understood.

Results: Here we show that through its expression in osteoblasts, one class II HDAC molecule, HDAC4, favors Osteocalcin expression, and as a result, the physiological functions regulated by osteocalcin such as spatial learning, memory, male fertility and insulin secretion. Molecular and genetic evidence indicates that through its expression in osteoblasts HDAC4 fulfills these long-range functions in part by stabilizing the transcription factor ATF4. Remarkably, through its expression in osteoblasts, HDAC4 also enhances appetite, a physiological function that is not regulated by osteocalcin.

Conclusions: These results provide a more in depth molecular understanding of the regulation of the endocrine functions of the osteoblast, and suggest the existence of additional hormones synthesized by osteoblasts that also regulate appetite.

No MeSH data available.


Related in: MedlinePlus