Two histone deacetylase inhibitors, trichostatin A and sodium butyrate, suppress differentiation into osteoclasts but not into macrophages

Abstract

Histone deacetylase (HDAC) inhibitors are emerging as a new class of anticancer therapeutic agents and have been demonstrated to induce differentiation in some myeloid leukemia cell lines. In this study, we show that HDAC inhibitors have a novel action on osteoclast differentiation. The effect of 2 HDAC inhibitors, trichostatin A (TSA) and sodium butyrate (NaB), on osteoclastogenesis was investigated using rat and mouse bone marrow cultures and a murine macrophage cell line RAW264. Both TSA and NaB inhibited the formation of preosteoclast-like cells (POCs) and multinucleated osteoclastlike cells (MNCs) in rat bone marrow culture. By reverse transcription-polymerase chain reaction analysis, TSA reduced osteoclastspecific mRNA expression of cathepsin K and calcitonin receptor (CTR). In contrast, TSA and NaB did not affect the formation of bone marrow macrophages (BMMs) induced by macrophage colony-stimulating factor as examined by nonspecific esterase staining. Fluorescence-activated cell sorting analysis showed that TSA did not affect the surface expression of macrophage markers for CD11b and F4/80 of BMMs. TSA and NaB also inhibited osteoclast formation and osteoclast-specific mRNA expression in RAW264 cells stimulated with receptor activator of nuclear factor-B (NF- B IntroductionHistone deacetylase (HDAC) inhibitors are known as agents that modulate the expression of genes by increasing histone acetylation, thereby regulating chromatin structure and transcription. 1,2 However, these inhibitors were not discovered based on their ability to inhibit HDAC activity. HDAC inhibitors include several structurally diverse natural products. Currently, there are several classes of HDAC inhibitors, including butyrate, hydroxamic acid, benzamide, and cyclic peptides. The simplest compound, butyrate, is a short-chain fatty acid derived from bacterial metabolism of dietary fiber in the colon. Butyrate was thought to be important for proper epithelial cell regulation, but was also found to have an antiproliferative and differentiation-inducing activity on various human colon carcinoma cells, normal cells, and neoplastic cells. [3][4][5] On the other hand, a hydroxamic acid, trichostatin A (TSA), is a more potent HDAC inhibitor that was identified as having potential therapeutic value against cancer in screens for agents that induce differentiation of murine erythroleukemia cells. 6,7 These HDAC inhibitors induce differentiation, inhibit cell proliferation, and induce apoptosis of tumor cells in cultures and animal models [3][4][5][6][7]8 and are emerging as a new class of potential therapeutic agents for the treatment of solid and hematologic malignancies.The effect of both sodium butyrate (NaB) and TSA on myeloid cell differentiation was well investigated using human promyelocytic leukemia cell lines, HL-60, U937, and a novel myeloid cell line, SN-1. 3,9,10 NaB treatment enhanced the promoter activity of a myeloid marker, the integrin CD11c/CD18 gene, in U937 cells and triggered differentiation of these 3 cell lines toward m...

HDAC3 and HDAC7 Have Opposite Effects on Osteoclast Differentiation

“…Suppression of HDAC3 Inhibits Osteoclast DifferentiationPrevious reports indicated that the non-selective HDAC inhibitors TSA and NaB inhibit osteoclast formation (13). However, these data do not indicate the significance of individual HDACs to osteoclastogenesis.…”

“…Several studies have shown that HDIs, TSA, and NaB directly inhibit osteoclastogenesis (13,14). The current study is among the first to identify the HDACs to be involved in this inhibitory effect on osteoclast formation.…”

“…HDIs, TSA, and NaB have been shown to inhibit receptor activator of NF-B ligand (RANKL)-mediated osteoclast differentiation due to inhibition of c-fos expression, NF-B-dependent transcription, and p38 MAP kinase activity (13,14). HDAC1 is recruited to the promoters of osteoclast genes by STAT3 and Eos-Mitf-Pu.1 complex (15,16).…”

CD38 is required for priming by TNF-α: a mechanism for extracellular coordination of cell fate

“…This finding may in part explain the clinically observed connection between CD38 expression in chronic lymphocytic leukemia and enhanced production of cytokines, such as IL-4 (17). Moreover, decreases in HDAC activity oppose osteoclast formation (27), thus providing another means through which CD38 hinders osteoclastogenesis.…”

The effect of novel anti-myeloma agents on bone metabolism of patients with multiple myeloma

“…96 It is already known that HDAC inhibitors, such as trichostatin A, sodium butyrate and FR901228, can block osteoclastogenesis. 97,98 Recently, another HDAC inhibitor, PXD 101, was also shown to inhibit osteoclast formation synergistically with bortezomib. 99 Finally, other proteasome inhibitors, such as MG-132 and MG-262, reduce both osteoclast differentiation and activity of mature osteoclasts in vitro; 78,100 and others, such as epoxomicin, PS-1 and lactacystin, induce osteoblast function and bone formation.…”