Better therapies to promote bone growth and regeneration are needed for many craniofacial, dental and orthopedic conditions. To improve our ability to clinically manipulate the formation of bone by osteoblasts will require a deeper understanding of the molecular mechanisms that govern their physiology. I have identified histone deacetylase 7 (HDAC7) as an important regulator of osteoblast differentiation that has potential implications for the development of new bone restorative therapies. HDAC7 is a transcriptional repressor in osteoblasts. Suppression of HDAC7 expression accelerated BMP2-stimulated osteoblast differentiation, suggesting that HDAC7 negatively regulates osteoblast differentiation. Therefore, antagonism of HDAC7 function would be anticipated to elicit a bone-anabolic response. Treatment with osteoblast precursors with BMP2 leads to export of HDAC7 from the nucleus, presumably relieving target genes from its repressive effects. My central hypothesis is that HDAC7 is recruited to the promoter of genes required for osteoblast differentiation by Runx2 and other transcription factors, where it associates with other regulators to bring about transcriptional repression. I further hypothesize that nuclear export of HDAC7 is necessary to allow osteoblast gene expression and cellular differentiation. I have developed HDAC7-overexpressing osteoblast-like cells that will enable me to test these hypotheses by two specific aims: 1) Define the effects of overexpressed and constitutively-nuclear HDAC7 on osteoblasts;and 2) Identify HDAC7-associated proteins in osteoblasts. Completion of these aims will improve our understanding of HDAC7's role in bone physiology and as a possible therapeutic target and as a mediator of BMP2 in craniofacial, orthopedic and dental applications.
Improved therapies are needed to facilitate treatment of the diseases and injuries that involve damage or malformation to bone of the craniofacial region. My previous work suggests that Histone Deacetylase 7 (HDAC7) inhibits differentiation of osteoblasts and revealed that HDAC7 is a target of bone morphogenic protein 2, which is currently used clinically to stimulate localized bone growth. This grant proposal will determine the functional role of HDAC7 and identify novel factors that cooperate with HDAC7 during skeletal growth. These results are important steps towards development of new therapeutic strategies for promoting bone growth and healing.
|Pham, Lan; Kaiser, Bria; Romsa, Amanda et al. (2011) HDAC3 and HDAC7 have opposite effects on osteoclast differentiation. J Biol Chem 286:12056-65|
|Pham, Lan; Beyer, Kayla; Jensen, Eric D et al. (2011) Bone morphogenetic protein 2 signaling in osteoclasts is negatively regulated by the BMP antagonist, twisted gastrulation. J Cell Biochem 112:793-803|