Inhibition of Histone Deacetylase Suppresses Osteoclastogenesis and Bone Destruction by Inducing IFN-β Production

Nakamura, Takahiro; Kukita, Toshio; Shobuike, Takeo; Nagata, Kazuhiro; Wu, Zhou; Ogawa, Kenji; Hotokebuchi, Takao; Kohashi, Osamu; Kukita, Akiko

doi:10.4049/jimmunol.175.9.5809

Cited by 100 publications

(96 citation statements)

References 53 publications

(63 reference statements)

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“…Earlier studies have shown that broadspectrum HDACi decrease survival and maturation of osteoclasts by inducing p21 expression without alterations to the p27 level, 23 blocking the RANKL signalling pathway or by increasing the mRNA level of IFN-b expression, an inhibitor of the osteoclastogenesis. 56 Furthermore, the HDACi, PDX101, in combination with bortezomib synergistically inhibits osteoclast formation in human BM cultures. The underlying mechanism of this synergism in vitro in osteoclast cells remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine models

et al. 2009

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Multiple myeloma (MM) is a B-cell malignancy, which often remains incurable because of the development of drug resistance governed by the bone marrow (BM) microenvironment. Novel treatment strategies are therefore urgently needed. In this study, we evaluated the anti-MM activity of JNJ-26481585, a novel 'second-generation' pyrimidyl-hydroxamic acid-based histone deacetylase inhibitor, using the syngeneic murine 5TMM model of MM. In vitro, JNJ-26481585 induced caspase cascade activation and upregulation of p21, resulting in apoptosis and cell cycle arrest in the myeloma cells at low nanomolar concentrations. Similar results could be observed in BM endothelial cells using higher concentrations, indicating the selectivity of JNJ-26481585 toward cancer cells. In a prophylactic and therapeutic setting, treatment with JNJ-26481585 resulted in an almost complete reduction of the tumor load and a significant decrease in angiogenesis. 5T2MM-bearing mice also developed a MM-related bone disease, characterized by increased osteoclast number, development of osteolytic lesions and a reduction in cancellous bone. Treatment of these mice with JNJ-264815 significantly reduced the development of bone disease. These data suggest that JNJ-26481585 has a potent anti-MM activity that can overcome the stimulatory effect of the BM microenvironment in vivo making this drug a promising new anti-MM agent.

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Section: Discussionmentioning

confidence: 99%

The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine models

et al. 2009

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“…[49][50][51] The continuous production of IFN-b by injection of IFN-b-expressing fibroblast or daily subcutaneous treatment with recombinant IFN-b inhibited inflammation as well as bone destruction in a system of collagen-induced arthritis in mice. 52,53 In addition, the expression of IFN-b was increased in synovial tissue of patients with RA.…”

Section: Discussionmentioning

confidence: 99%

A possible suppressive role of galectin-3 in upregulated osteoclastogenesis accompanying adjuvant-induced arthritis in rats

Kukita

Teramachi

et al. 2009

Laboratory Investigation

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Galectin-3 is a b-galactoside-binding animal lectin having pleiotropic effects on cell growth, differentiation, and apoptosis. This lectin has been shown to be involved in phagocytosis by macrophages and in inflammation. Here we investigated an involvement of galectin-3 in the regulatory process of inflammatory bone resorption in rats with adjuvant-induced arthritis (AA rats) accompanying severe bone destruction in the ankle joints. The protein level of galectin-3 in the ankle-joint extracts was markedly augmented at week 3 after adjuvant injection, at the time when severe bone destruction was observed. Immunohistochemical analysis revealed an extremely high expression of galectin-3 in macrophages and granulocytes infiltrated in the area of severe bone destruction. To estimate the role of galectin-3 in osteoclastogenesis and osteoclastic bone resorption, recombinant galectin-3 was added to in vitro culture systems. Galectin-3 markedly inhibited the formation of osteoclasts in cultures of murine osteoclast precursor cell line as well as in rat bone marrow culture systems. This inhibition was not observed by heat-inactivated galectin-3 or by galectin-7. Although recombinant galectin-3 did not affect signaling through mitogen-activated protein kinase (MAPK) or nuclear factor-kB (NF-kB), it specifically suppressed the induction of nuclear factor of activated T-cells c1 (NFATc1). Galectin-3 significantly inhibited dentine resorption by mature osteoclasts in vitro. Furthermore, in vivo studies clearly showed a significant suppression of bone destruction and osteoclast recruitment accompanying arthritis, when galectin-3 was injected into the cavity of ankle joint of AA rats. Thus, abundant galectin-3 observed in the area of severe bone destruction may act as a negative regulator for the upregulated osteoclastogenesis accompanying inflammation to prevent excess bone destruction.

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“…20,21 Briefly, 5-week-old female Lewis rats were intradermally injected at the base of the tail with complete adjuvant consisting of 25 mg/kg heat-killed M. butyricum (Difco Laboratories) suspended in mineral oil. In control experiments, rats were injected with mineral oil alone.…”

Section: Preparation Of Rat Primary Osteoblastsmentioning

confidence: 99%

Adenosine abolishes MTX-induced suppression of osteoclastogenesis and inflammatory bone destruction in adjuvant-induced arthritis

Teramachi

Kukita

et al. 2011

Laboratory Investigation

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Methotrexate (MTX) is widely utilized for the treatment of patients with rheumatoid arthritis (RA); however, recent observation of the MTX-resistant patients proposed some difficulty in MTX-dependent therapeutic approach for RA. To access cellular events related to MTX resistance in RA in respect to inflammatory bone destruction, we investigated on an involvement of the potent inflammatory mediator adenosine in the regulation of osteoclastogenesis and inflammatory bone destruction. In rats with adjuvant-induced arthritis (AA rats), MTX efficiently suppressed bone destruction when it was administrated within 3 days after adjuvant injection, while it could not suppress inflammatory bone destruction if MTX was injected at the time of onset of inflammation (at day 10 after adjuvant injection). Time-course change in the level of plasma adenosine of AA rats was estimated by use of high-performance liquid chromatography and elucidated that adenosine level was markedly elevated till 10 days after adjuvant injection. In vitro bone marrow culture system for evaluating osteoclastogenesis, MTX markedly suppressed osteoclastogenesis in a stromal cell-dependent manner. This MTX-induced suppression of osteoclastogenesis was abrogated by the addition of adenosine. MTX suppressed the expression of mRNA for the receptor activator NF-kB ligand (RANKL), but it did not suppress the expression of osteoprotegerin (OPG). The addition of MTX and adenosine together markedly suppressed the level of OPG expression. Abolishment of MTX action by adenosine was significantly blocked by MRS1754, a highly selective antagonist for the A 2b adenosine receptor (A 2b AR), but not by caffeine, an antagonist for A 1 , A 2a , A 3 AR (A 1 AR, A 2a AR, and A 3 AR), which suggests that adenosine acts through A 2b AR. Immunohistochemical studies showed abundant expression of A 2b AR in cells localized in the bone-bone marrow boundary of the distal tibia in AA rats but not in control rats. When adenosine was injected in the ankle joints of MTX-treated AA rats, the suppressive effects of MTX on bone destruction was abolished. The current data therefore suggest that upregulation of adenosine production abolished the suppressive effect of MTX on osteoclastic bone destruction. Involvement of the adenosine-A 2b AR system may explain MTX resistance in RA.

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Inhibition of Histone Deacetylase Suppresses Osteoclastogenesis and Bone Destruction by Inducing IFN-β Production

Cited by 100 publications

References 53 publications

The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine models

The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine models

A possible suppressive role of galectin-3 in upregulated osteoclastogenesis accompanying adjuvant-induced arthritis in rats

Adenosine abolishes MTX-induced suppression of osteoclastogenesis and inflammatory bone destruction in adjuvant-induced arthritis

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