Histone deacetylases in bone development and skeletal disorders

Elizabeth W. Bradley, Lomeli R. Carpio, Andre J. Van Wijnen, Meghan Elizabeth McGee Lawrence, Jennifer J. Westendorf

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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 Zn2+ 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 immobilizationrelated 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.

Original languageEnglish (US)
Pages (from-to)1359-1381
Number of pages23
JournalPhysiological Reviews
Volume95
Issue number4
DOIs
StatePublished - Sep 9 2015

Fingerprint

Sirtuins
Histone Deacetylases
Bone Development
Bone and Bones
Bone Density
Protein Stability
Poisons
Osteoclasts
Human Genome
United States Food and Drug Administration
Tissue Engineering
Bone Resorption
Chondrocytes
Osteoblasts
Osteogenesis
Epigenomics
Skeleton
DNA Repair
Histones
Lysine

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Physiology (medical)

Cite this

Bradley, E. W., Carpio, L. R., Van Wijnen, A. J., McGee Lawrence, M. E., & Westendorf, J. J. (2015). Histone deacetylases in bone development and skeletal disorders. Physiological Reviews, 95(4), 1359-1381. https://doi.org/10.1152/physrev.00004.2015

Histone deacetylases in bone development and skeletal disorders. / Bradley, Elizabeth W.; Carpio, Lomeli R.; Van Wijnen, Andre J.; McGee Lawrence, Meghan Elizabeth; Westendorf, Jennifer J.

In: Physiological Reviews, Vol. 95, No. 4, 09.09.2015, p. 1359-1381.

Research output: Contribution to journalArticle

Bradley, EW, Carpio, LR, Van Wijnen, AJ, McGee Lawrence, ME & Westendorf, JJ 2015, 'Histone deacetylases in bone development and skeletal disorders', Physiological Reviews, vol. 95, no. 4, pp. 1359-1381. https://doi.org/10.1152/physrev.00004.2015
Bradley, Elizabeth W. ; Carpio, Lomeli R. ; Van Wijnen, Andre J. ; McGee Lawrence, Meghan Elizabeth ; Westendorf, Jennifer J. / Histone deacetylases in bone development and skeletal disorders. In: Physiological Reviews. 2015 ; Vol. 95, No. 4. pp. 1359-1381.
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