Class II and IV HDACs function as inhibitors of osteoclast differentiation

Abstract

Histone deacetylases (HDACs) are negative regulators of transcription and have been shown to regulate specific changes in gene expression. In vertebrates, eighteen HDACs have thus far been identified and subdivided into four classes (I-IV). Key roles for several HDACs in bone development and biology have been elucidated through in vitro and in vivo models. By comparison, there is a paucity of data on the roles of individual HDACs in osteoclast formation and function. In this study, we investigated the gene expression patterns and the effects of suppressing individual class II (Hdac4, 5, 6, 9, and 10) and class IV (Hdac11) HDACs during osteoclast differentiation. We demonstrated that HDAC class II and IV members are differentially expressed during osteoclast differentiation. Additionally, individual shRNA-mediated suppression of Hdac4, 5, 9, 10 and 11 expression resulted in increased multinucleated osteoclast size and demineralization activity, with little to no change in the overall number of multinucleated osteoclasts formed compared with control shRNA-treated cells. We also detected increased expression of genes highly expressed in osteoclasts, including c-Fos, Nfatc1, Dc-stamp and Cathepsin K. These observations indicate that HDACs cooperatively regulate shared targets in a non-redundant manner.

Epigenetic Regulators Involved in Osteoclast Differentiation

“…HDAC4 is expressed in osteoclast precursor cells and decreases in expression as osteoclasts progress through differentiation [ 37 ]. Additionally, knockdown of HDAC4 in osteoclasts results in enhanced differentiation and upregulation of osteoclast genes [ 37 ].…”

“…HDAC4 is expressed in osteoclast precursor cells and decreases in expression as osteoclasts progress through differentiation [ 37 ]. Additionally, knockdown of HDAC4 in osteoclasts results in enhanced differentiation and upregulation of osteoclast genes [ 37 ]. More focused analysis by the Mansky lab is currently being performed to determine the role and significance of HDAC4 in vivo during osteoclast differentiation and skeletal modeling and remodeling.…”

“…The in vivo role of HDAC5 in regulating osteoclast differentiation has not been determined; however, it is an area that the Mansky lab is actively investigating [ 38 , 39 ]. Studies with shRNAs targeting HDAC5 resulted in enhanced osteoclast differentiation and activity [ 37 ]. PCAF has been shown to acetylate NFATc1 the master regulator of osteoclast differentiation enhancing its stability.…”

“…HDAC6 expression peaks during osteoclast fusion and is expressed abundantly in the cytoplasm [ 37 ]. Interestingly, knockdown of HDAC6 in osteoclasts does not seem to have a significant effect on osteoclast differentiation [ 37 ].…”

“…HDAC6 expression peaks during osteoclast fusion and is expressed abundantly in the cytoplasm [ 37 ]. Interestingly, knockdown of HDAC6 in osteoclasts does not seem to have a significant effect on osteoclast differentiation [ 37 ]. However, research shows that HDAC6 plays an important role in destabilizing the osteoclast cytoskeleton and inhibiting osteoclast migration and podosome formation [ 40 , 41 ].…”