Osteoclast differentiation independent of the TRANCE–RANK–TRAF6 axis

Kim, Nacksung,Kadono, Yuho,Takami, Masamichi,Lee, Junwon,Lee, Seoung-Hoon,Okada, Fumihiko,Kim, Jung Ha,Kobayashi, Takashi,Odgren, Paul R.,Nakano, Hiroyasu,Yeh, Wen-Chen,Lee, Sun-Kyeong,Lorenzo, Joseph The Rockefeller University Press 2005 The Journal of experimental medicine Vol.202 No.5

<P>Osteoclasts are derived from myeloid lineage cells, and their differentiation is supported by various osteotropic factors, including the tumor necrosis factor (TNF) family member TNF-related activation-induced cytokine (TRANCE). Genetic deletion of TRANCE or its receptor, receptor activator of nuclear factor <B>κ</B>B (RANK), results in severely osteopetrotic mice with no osteoclasts in their bones. TNF receptor-associated factor (TRAF) 6 is a key signaling adaptor for RANK, and its deficiency leads to similar osteopetrosis. Hence, the current paradigm holds that TRANCE–RANK interaction and subsequent signaling via TRAF6 are essential for the generation of functional osteoclasts. Surprisingly, we show that hematopoietic precursors from TRANCE-, RANK-, or TRAF6-null mice can become osteoclasts in vitro when they are stimulated with TNF-<B>α</B> in the presence of cofactors such as TGF-<B>β</B>. We provide direct evidence against the current paradigm that the TRANCE–RANK–TRAF6 pathway is essential for osteoclast differentiation and suggest the potential existence of alternative routes for osteoclast differentiation.</P>

MafB negatively regulates RANKL-mediated osteoclast differentiation

Kim, Nacksung 이화여자대학교 세포신호전달연구센터 2008 고사리 세포신호전달 심포지움 Vol. No.10

Receptor activator of nuclear factor ĸB ligand(RANKL) induces osteoclast formation from hematopoietic cells via regulation of various transcription factors. Here, we show that MafB negatively regulates RANKL-induced osteoclast differentiation. Expression levels of MafB are significantly reduced by RANKL during osteoclastogenesis. Overexpression of MafB in bone marrow-derived monocyte/macrophage lineage cells(BMMs) inhibits the· formation of TRAP-positive multinuclear osteoclasts, but phagocytic activity of BMMs is retained. Furthermore, overexpression of MafB in BMMs attenuates the gene induction of NFATc1 and osteoclast-associated receptor(OSCAR) during RANKL-mediated osteoclastogenesis. In addition, MafB proteins interfere with the DNA binding ability of c-fos, Mitf, and NFATcl, inhibiting their transactivation of NFATc1 and OSCAR. Furthermore, reduced expression of MafB by RNAi enhances osteoclastogenesis and increases expression of NFATcl and OSCAR. Taken together, our results suggest that MafB can act as an important modulator of RANKL-mediated osteoclastogenesis. Therefore, further investigation of the detailed mechanism of MafB gene regulation will provide beneficial strategies for alternative therapies for the treatment of bone diseases such as osteoporosis and rheumatoid arthritis.

Vaccination with DNA Encoding Human T-Cell Epitopes Suppresses Der p Induced Allergic Responses in Mice

Kwon, Soon,Nacksung, Kim,Yoo, Tae-June Taylor Francis 2005 The Journal of asthma Vol.42 No.2

<P>The apparent complexity of allergen-specific T-cell response in terms of epitope usage in humans is a potential barrier to peptide-based immunotherapy for allergy. A knowledge of cross-reacting T-cell epitopes of common allergens might have an impact on the development of vaccines for immunotherapy. We examined the efficiency of vaccinating with plasmid DNA coding only human T-cell epitopes on the suppression of allergic reactions in mice. BALB/c mice that received an injection of mixed naked DNA plasmids encoding the five classes of human T-cell epitopes on Der p 1 and Der p 2 produced a significant reduction in total and Der p-specific immunoglobulin E (IgE) synthesis. In Der p specific-IgG2a antibody responses, vaccinated mice showed more prominent responses than controls. Higher levels of interferon-?, a Th1 cytokine associated with the suppression of IgE production, were found in the sera of vaccinated mice. Histologic studies showed a marked reduction in the infiltration of inflammatory cells in the lung tissues of vaccinated mice vs. controls. These results suggest that vaccination with DNA encoding human T-cell epitopes effectively inhibits allergic responses in mice and might induce cross-regulation on helper T-cell level in vivo.</P>

Osteoimmunology : Interplay Between the Immune System and Bone Metabolism

C.Walsh, Matthew,Kim, Nacksung,Kadono, Yuho,Rho, Jaerang,Lee, Soo Young,Lorenzo, Joseph,Choi, Yongwon 충남대학교 형질전환복제돼지연구센터 2007 논문집 Vol. No.10

Studies of bone and the immune system have converged in recent years under the banner of osteoimmunology. The immune system is spawned in the bone marrow reservoir, and investigators now recognize that important niches also exist there for memory lymphocytes. At the same time, various factors produced during immune responses are capable of profoundly affecting regulation of bone. Mechanisms have evolved to prevent excessive interference by thc immune system with bone homeostasis, yet pathologic bone loss is a common sequela associated with autoimmunity and cancer. There are also developmental links, or parallels, between bone and the immune system. Cells that regulate bone turnover share a common precursor with inflammatory immune cells and may restrict themselves anatomically, in part by utilizing a signaling network analo￢gous to lymphocyte costimulation. Efforts are currently under way to further characterize how these two organ systems overlap and to develop therapeutic strategies that benefit from this understanding.

Pro-inflammatory Cytokines Modulating Osteoclast Differentiation and Function

( Semun Seong ),( Jung Ha Kim ),( Nacksung Kim ) 대한류마티스학회 2016 대한류마티스학회지 Vol.23 No.3

In general, bone homeostasis is maintained through the balance between bone formation and resorption. Disruption in this balance results in bone-related diseases such as osteopetrosis, osteoporosis, and rheumatoid arthritis. Often, enhanced osteoclastogenesis is followed by accelerated bone resorption that is induced by pro-inflammatory cytokines in osteoporosis or rheumatoid arthritis, and leads to bone destruction. In this review study, factors involved in osteoclast differentiation and function are discussed, and how the prevention of such factors is effective in ameliorating bone loss in osteoporosis or rheumatoid arthritis. (J Rheum Dis 2016;23:148-153)

Negative regulators in RANKL-induced osteoclastogenesis

Lee, Junwon,Kim, Kabsun,Kim, Nacksung 대한구강생물학회 2007 International Journal of Oral Biology Vol.32 No.1

Receptor activator of nuclear factor kB ligand (RANKL) induces osteoclast formation from hematopoietic cells via up-regulation of positive regulators, including NF-kB, cFos, microphthalmia transcription factor (Mitf), PU.1, and nuclear factor of activated T cells (NFAT) c1. In addition to the positive regulation by these transcription factors, RANKL appears to regulate negative regulators such as MafB and inhibitors of differentiation (Ids). Ids and MafB are abundantly expressed in osteoclast precursors, bone marrowderived monocyte/macrophage lineage cells (BMMs). Expression levels of these genes are significantly reduced by RANKL during osteoclastogenesis. Overexpression of these genes in BMMs inhibits the formation of tartarate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts by down-regulation of NFATcl and osteoclast-associated receptor (OSCAR), which are important for osteoclast differentiation. Furthermore, reduced expression of these genes enhances osteoclastogenesis and increases expression of NFATc1 and OSCAR. Taken together, RANKL induces osteoclastogenesis via up-regulation of positive regulators as well as down-regulation of negative regulators.

IRF2 enhances RANKL-induced osteoclast differentiation via regulating NF-κB/NFATc1 signaling

( Inyoung Kim ),( Jung Ha Kim ),( Kabsun Kim ),( Semun Seong ),( Keun-bae Lee ),( Nacksung Kim ) 생화학분자생물학회 2021 BMB Reports Vol.54 No.9

Interferon regulatory factors (IRFs) play roles in various biological processes including cytokine signaling, cell growth regulation and hematopoietic development. Although it has been reported that several IRFs are involved in bone metabolism, the role of IRF2 in bone cells has not been elucidated. Here, we investigated the involvement of IRF2 in RANKL-induced osteoclast differentiation. IRF2 overexpression in osteoclast precursor cells enhanced osteoclast differentiation by regulating the expression of NFATc1, a master regulator of osteoclastogenesis. Conversely, IRF2 knockdown inhibited osteoclast differentiation and decreased the NFATc1 expression. Moreover, IRF2 increased the translocation of NF-κB subunit p65 to the nucleus in response to RANKL and subsequently induced the expression of NFATc1. IRF2 plays an important role in RANKL-induced osteoclast differentiation by regulating NF-κB/NFATc1 signaling pathway. Taken together, we demonstrated the molecular mechanism of IRF2 in osteoclast differentiation, and provide a molecular basis for potential therapeutic targets for the treatment of bone diseases characterized by excessive bone resorption. [BMB Reports 2021; 54(9): 482-487]

Ginsenoside Rg2 inhibits osteoclastogenesis by downregulating the NFATc1, c-Fos, and MAPK pathways

Sung-Hoon Lee,Shin-Young Park,Jung Ha Kim,Nacksung Kim,Junwon Lee 생화학분자생물학회 2023 BMB Reports Vol.56 No.10

Ginsenosides, among the most active components of ginseng,exhibit several therapeutic effects against cancer, diabetes, andother metabolic diseases. However, the molecular mechanismunderlying the anti-osteoporotic activity of ginsenoside Rg2, amajor ginsenoside, has not been clearly elucidated. This studyaimed to determine the effects of ginsenoside Rg2 on receptoractivator of nuclear factor-κB ligand (RANKL)-induced osteoclastformation. Results indicate that ginsenoside Rg2 inhibits RANKLinducedosteoclast differentiation of bone marrow macrophages(BMMs) without cytotoxicity. Pretreatment with ginsenoside Rg2significantly reduced the RANKL-induced gene expression ofc-fos and nuclear factor of activated T-cells (Nfatc1), as well asosteoclast-specific markers tartrate-resistant acid phosphatase(TRAP, Acp5) and osteoclast-associated receptor (Oscar). Moreover,RANKL-induced phosphorylation of mitogen-activated proteinkinases (MAPKs) was decreased by ginsenoside Rg2 in BMM. Therefore, we suggest that ginsenoside Rg2 suppresses RANKLinducedosteoclast differentiation through the regulation of MAPKsignaling-mediated osteoclast markers and could be developedas a therapeutic drug for the prevention and treatment of osteoporosis.

Osteoblasts support B-lymphocyte commitment and differentiation from hematopoietic stem cells

Zhu, Jiang,Garrett, Russell,Jung, Younghun,Zhang, Yi,Kim, Nacksung,Wang, Jingcheng,Joe, Gerard J.,Hexner, Elizabeth,Choi, Yongwon,Taichman, Russell S.,Emerson, Stephen G. American Society of Hematology 2007 Blood Vol.109 No.9

<B>Abstract</B><P>Early B lymphopoiesis in mammals is induced within the bone marrow (BM) microenvironment, but which cells constitute this niche is not known. Previous studies had shown that osteoblasts (OBs) support hematopoietic stem cell (HSC) proliferation and myeloid differentiation. We now find that purified primary murine OBs also support the differentiation of primitive hematopoietic stem cells through lymphoid commitment and subsequent differentiation to all stages of B-cell precursors and mature B cells. Lin−Sca-1+Rag-2− BM cell differentiation to B cells requires their attachment to OBs in vitro, and this developmental process is mediated via VCAM-1, SDF-1, and IL-7 signaling induced by parathyroid hormone (PTH). Addition of cytokines produced by nonosteoblastic stromal cells (c-Kit ligand, IL-6, and IL-3) shifted the cultures toward myelopoiesis. Confirming the role of OBs in B lymphopoiesis, we found that selective elimination of osteoblasts in Col2.3Δ-TK transgenic mice severely depleted pre-pro-B and pro-B cells from BM, preceding any decline in HSCs. Taken together, these results demonstrate that osteoblasts are both necessary and sufficient for murine B-cell commitment and maturation, and thereby constitute the cellular homolog of the avian bursa of Fabricius.</P>

GATA4 negatively regulates bone sialoprotein expression in osteoblasts

( Insun Song ),( Byung-chul Jeong ),( Yong Jun Choi ),( Yoon-sok Chung ),( Nacksung Kim ) 생화학분자생물학회(구 한국생화학분자생물학회) 2016 BMB Reports Vol.49 No.6

GATA4 has been reported to act as a negative regulator in osteoblast differentiation by inhibiting the Dlx5 transactivation of Runx2 via the attenuation of the binding ability of Dlx5 to the Runx2 promoter region. Here, we determine the role of GATA4 in the regulation of bone sialoprotein (Bsp) in osteoblasts. We observed that the overexpression of Runx2 or Sox9 induced the Bsp expression in osteoblastic cells. Silencing GATA4 further enhanced the Runx2- and Sox9-mediated Bsp promoter activity, whereas GATA4 overexpression down-regulated Bsp promoter activity mediated by Runx2 and Sox9. GATA4 also interacted with Runx2 and Sox9, by attenuating the binding ability of Runx2 and Sox9 to the Bsp promoter region. Our data suggest that GATA4 acts as a negative regulator of Bsp expression in osteoblasts. [BMB Reports 2016; 49(6): 343-348]