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Histone deacetylases in skeletal development and bone mass maintenance.

ABSTRACT: The skeleton is a multifunctional and regenerative organ. Dynamic activities within the bone microenvironment necessitate and instigate rapid and temporal changes in gene expression within the cells (osteoclasts, osteoblasts, and osteocytes) responsible for skeletal maintenance. Regulation of gene expression is controlled, in part, by histone deacetylases (Hdacs), which are intracellular enzymes that directly affect chromatin structure and transcription factor activity. Key roles for several Hdacs in bone development and biology have been elucidated though in vitro and in vivo models. Recent findings suggest that clinical usage of small molecule Hdac inhibitors for conditions like epilepsy, bipolar disorder, cancer, and a multitude of other ailments may have unintended effects on bone cell populations. Here we review the progress that has been made in the last decade in understanding how Hdacs contribute to bone development and maintenance.

SUBMITTER: McGee-Lawrence ME

PROVIDER: S-EPMC3046313 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Histone deacetylases in skeletal development and bone mass maintenance.

McGee-Lawrence Meghan E ME Westendorf Jennifer J JJ

Gene 20101222 1-2

The skeleton is a multifunctional and regenerative organ. Dynamic activities within the bone microenvironment necessitate and instigate rapid and temporal changes in gene expression within the cells (osteoclasts, osteoblasts, and osteocytes) responsible for skeletal maintenance. Regulation of gene expression is controlled, in part, by histone deacetylases (Hdacs), which are intracellular enzymes that directly affect chromatin structure and transcription factor activity. Key roles for several Hda ...[more]

PMID: 21185361

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Project description:Histone deacetylases (Hdacs) are conserved enzymes that remove acetyl groups from lysine side chains in histones and other proteins. Eleven of the 18 Hdacs encoded by the human and mouse genomes depend on Zn(2+) for enzymatic activity, while the other 7, the sirtuins (Sirts), require NAD2(+). Collectively, Hdacs and Sirts regulate numerous cellular and mitochondrial processes including gene transcription, DNA repair, protein stability, cytoskeletal dynamics, and signaling pathways to affect both development and aging. Of clinical relevance, Hdacs inhibitors are United States Food and Drug Administration-approved cancer therapeutics and are candidate therapies for other common diseases including arthritis, diabetes, epilepsy, heart disease, HIV infection, neurodegeneration, and numerous aging-related disorders. Hdacs and Sirts influence skeletal development, maintenance of mineral density and bone strength by affecting intramembranous and endochondral ossification, as well as bone resorption. With few exceptions, inhibition of Hdac or Sirt activity though either loss-of-function mutations or prolonged chemical inhibition has negative and/or toxic effects on skeletal development and bone mineral density. Specifically, Hdac/Sirt suppression causes abnormalities in physiological development such as craniofacial dimorphisms, short stature, and bone fragility that are associated with several human syndromes or diseases. In contrast, activation of Sirts may protect the skeleton from aging and immobilization-related bone loss. This knowledge may prolong healthspan and prevent adverse events caused by epigenetic therapies that are entering the clinical realm at an unprecedented rate. In this review, we summarize the general properties of Hdacs/Sirts and the research that has revealed their essential functions in bone forming cells (e.g., osteoblasts and chondrocytes) and bone resorbing osteoclasts. Finally, we offer predictions on future research in this area and the utility of this knowledge for orthopedic applications and bone tissue engineering.

Project description:Adult Ibsp-knockout mice (BSP-/-) display shorter stature, lower bone turnover and higher trabecular bone mass than wild type, the latter resulting from impaired bone resorption. Unexpectedly, BSP knockout also affects reproductive behavior, as female mice do not construct a proper "nest" for their offsprings. Multiple crossing experiments nonetheless indicated that the shorter stature and lower weight of BSP-/- mice, since birth and throughout life, as well as their shorter femur and tibia bones are independent of the genotype of the mothers, and thus reflect genetic inheritance. In BSP-/- newborns, µCT analysis revealed a delay in membranous primary ossification, with wider cranial sutures, as well as thinner femoral cortical bone and lower tissue mineral density, reflected in lower expression of bone formation markers. However, trabecular bone volume and osteoclast parameters of long bones do not differ between genotypes. Three weeks after birth, osteoclast number and surface drop in the mutants, concomitant with trabecular bone accumulation. The growth plates present a thinner hypertrophic zone in newborns with lower whole bone expression of IGF-1 and higher IHH in 6 days old BSP-/- mice. At 3 weeks the proliferating zone is thinner and the hypertrophic zone thicker in BSP-/- than in BSP+/+ mice of either sex, maybe reflecting a combination of lower chondrocyte proliferation and impaired cartilage resorption. Six days old BSP-/- mice display lower osteoblast marker expression but higher MEPE and higher osteopontin(Opn)/Runx2 ratio. Serum Opn is higher in mutants at day 6 and in adults. Thus, lack of BSP alters long bone growth and membranous/cortical primary bone formation and mineralization. Endochondral development is however normal in mutant mice and the accumulation of trabecular bone observed in adults develops progressively in the weeks following birth. Compensatory high Opn may allow normal endochondral development in BSP-/- mice, while impairing primary mineralization.

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Histone deacetylases in skeletal development and bone mass maintenance.

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Histone deacetylases in skeletal development and bone mass maintenance.

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