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

Abstract

ObjectiveThe 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.MethodsIn contrast, the role of chromatin remodeling enzymes, such as histone deacetylases (HDACs), in this process has not as yet been thoroughly understood.ResultsHere 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.ConclusionsThese 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.

MicroRNA-29a mitigates glucocorticoid induction of bone loss and fatty marrow by rescuing Runx2 acetylation

“…HDAC4 reportedly inhibits parathyroid hormone-induced promotion of osteogenic activities [37] and regulates energy expenditures in mice [38]. In addition, loss of β-catenin signaling was observed to accelerate osteogenic progenitor cells differentiation into adipocytes [39].…”

The “soft” side of the bone: unveiling its endocrine functions

“…This variable was not affected in Ocn −/− mice. The changes in food intake were not due to changes in leptin levels [131].…”

“…HDAC4 accumulates in osteoblasts' nuclei , associates with ATF4 and is able to increase ATF4-dependent RANKL expression in osteoblasts following sympathetic stimulation [130]. In a recent work by Makinistoglu and Karsenty [131], HDAC4 has also been demonstrated to control Ocn expression, therefore working as an integrator of extracellular stimuli, such as sympathetic tone, that regulates Ocn expression. But this is not the end of the story: the energy metabolism of HDAC4 obs −/− mice is similar to that of Ocn −/− mice, yet not identical [131].…”

“…In a recent work by Makinistoglu and Karsenty [131], HDAC4 has also been demonstrated to control Ocn expression, therefore working as an integrator of extracellular stimuli, such as sympathetic tone, that regulates Ocn expression. But this is not the end of the story: the energy metabolism of HDAC4 obs −/− mice is similar to that of Ocn −/− mice, yet not identical [131]. The most relevant change in energy metabolism was that HDAC4 obs−/− mice have a significantly lower food intake, and consequently a lower body weight, compared to WT.…”

Searching for additional endocrine functions of the skeleton: genetic approaches and implications for therapeutics

“…For example, ablation of osteoblasts in adult mice resulted in both Osteocalcin−/− mice like metabolic phenotypes, such as hypoinsulinemia, hyperglycemia, glucose intolerance, and insulin resistance, and osteocalcin-independent abnormalities, such as increased energy expenditure and the expression of resistin [135]. Similarly, mice with osteoblast-specific knockout of HDAC4, a class II histone deacetylase favoring Osteocalcin expression by stabilizing the transcription factor ATF4, developed osteocalcin-deficient phenotypes, such as impaired spatial learning, memory, male fertility and insulin secretion, however, they also showed decreased appetite, a physiological function that is not regulated by osteocalcin [136]. Gillespie et al .…”