RANKL-induced DC-STAMP Is Essential for Osteoclastogenesis

Kukita, Toshio; Wada, Naohisa; Kukita, Akiko; Kakimoto, Takashi; Sandra, Ferry; Toh, Kazuko; Nagata, Kazuhiro; Iijima, Tadahiko; Horiuchi, Madoka; Matsusaki, Hiromi; Hieshima, Kunio; Yoshie, Osamu; Nomiyama, Hisayuki

doi:10.1084/jem.20040518

Cited by 337 publications

(281 citation statements)

References 24 publications

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“…(3) DC-STAMP was originally identified as a seventransmembrane protein expressed in dendritic cells (22) and then subsequently in interleukin 4 (IL-4)-induced macrophages and osteoclasts. (3,23,24) Transgenic mice overexpressing DC-STAMP under control of the actin promoter do not show ectopic cell-cell fusion, confirming that DC-STAMP is specifically for macrophage cell-cell fusion. (25) Interestingly, DC-STAMP overexpression in macrophage colony-stimulating factor (M-CSF)-induced macrophages does not induce cell-cell fusion, although DC-STAMP was identified in a subtractive screen between M-CSF-induced mononuclear macrophages and M-CSF plus receptor activator of NF-kB ligand (RANKL)-induced multinuclear osteoclasts.…”

Section: Introductionmentioning

confidence: 83%

Osteoclast stimulatory transmembrane protein and dendritic cell–specific transmembrane protein cooperatively modulate cell–cell fusion to form osteoclasts and foreign body giant cells

Miyamoto

Suzuki

Miyauchi

et al. 2012

Journal of Bone and Mineral Research

151

135

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Cell-cell fusion is a dynamic phenomenon promoting cytoskeletal reorganization and phenotypic changes. To characterize factors essential for fusion of macrophage lineage cells, we identified the multitransmembrane protein, osteoclast stimulatory transmembrane protein (OC-STAMP), and analyzed its function. OC-STAMP-deficient mice exhibited a complete lack of cell-cell fusion of osteoclasts and foreign body giant cells (FBGCs), both of which are macrophage-lineage multinuclear cells, although expression of dendritic cell specific transmembrane protein (DC-STAMP), which is also essential for osteoclast/FBGC fusion, was normal. Crossing OC-STAMP-overexpressing transgenic mice with OC-STAMP-deficient mice restored inhibited osteoclast and FBGC cell-cell fusion seen in OC-STAMP-deficient mice. Thus, fusogenic mechanisms in macrophage-lineage cells are regulated via OC-STAMP and DC-STAMP. ß

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Section: Introductionmentioning

confidence: 83%

Osteoclast stimulatory transmembrane protein and dendritic cell–specific transmembrane protein cooperatively modulate cell–cell fusion to form osteoclasts and foreign body giant cells

Miyamoto

Suzuki

Miyauchi

et al. 2012

Journal of Bone and Mineral Research

151

135

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“…We also investigated known osteoclast fusion genes. Dendritic cellspecific transmembrane protein (dc-stamp), the major fusion gene and also an NFATc1 target gene (36), was inhibited in the GW3965-treated BMM (Fig. 2C).…”

Section: Effects Of Gw3965 On Osteoclast Differentiation Genes-tomentioning

confidence: 95%

Activation of Liver X Receptor (LXR) Inhibits Receptor Activator of Nuclear Factor κB Ligand (RANKL)-induced Osteoclast Differentiation in an LXRβ-dependent Mechanism

Remen

Henning

Lerner

et al. 2011

Journal of Biological Chemistry

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Bone destruction is the major pathological process in many bone metabolic diseases and is a result of increased osteoclast formation and bone resorption. The liver X receptors (␣,␤), important regulators of cholesterol metabolism and inflammatory signaling, have recently been observed to play a role in both physiological and pathological bone turnover. However, the relationship between liver X receptors (LXR) and osteoclast differentiation/formation remains unknown. Here, we report that the LXR ligand GW3965 is able to clearly and potently inhibit the formation of mature osteoclasts from receptor activator of nuclear factor B ligand (RANKL)-stimulated human and murine osteoclast precursors. This results in a significant inhibition of bone resorption. We observed that GW3965 significantly inhibited expression of the osteoclast markers tartrateresistant acid phosphatase, cathepsin K, osteoclast-associated receptor (OSCAR), and calcitonin receptor, appearing to act in an NFATc1/p38/microphthalmia-associated transcription factor (MITF)-dependent mechanism, independently of receptor activator of nuclear factor B or c-Fos and not directly involving the NFB pathways. GW3965 was less effective in RAW264.7 monocyte/macrophage cells, which are more committed into the osteoclast lineage. Also, GW3965 seemed to act differently depending on the source of the progenitor cells as it had no effect on calvarial osteoclasts, compared with marrow or bloodderived monocytes. As these effects were abolished in osteoclast precursors derived from LXR␤ ؊/؊ mice, we suggest that GW3965 acts via an LXR␤-dependent mechanism. Taken together, our results suggest that the LXR can act as an important inhibitor of RANKL-mediated osteoclast differentiation.Bone remodeling occurs continuously throughout life to maintain bone quality in response to mechanical stress and hormonal regulation. To retain a normal bone mass, bone is resorbed by osteoclasts, and new bone matrix is deposited by osteoblasts in a tightly coupled process. Imbalances in this process can lead to excessive resorption by the osteoclasts and increased bone fragility, as observed in many common skeletal diseases (osteoporosis, metastatic bone disease, and Paget disease of bone) (1, 2). Osteoclasts are multinucleated giant cells derived from the pluripotent hematopoietic stem cell lineage. Differentiation of the precursor cells into the osteoclast lineage is principally regulated by macrophage colony-stimulating factor (M-CSF) and receptor activator of NFB ligand (RANKL) 2 (3). Binding of RANKL to its receptor RANK activates different signaling cascades (NFB, MAPK, and Ca 2ϩ oscillation/calcineurin) to induce nuclear factor of activated T cells c1 (NFATc1), the key transcription factor in osteoclastogenesis (4, 5). NFATc1 in turn induces the transcription of osteoclast-specific genes, including tartrate-resistant acid phosphatase (TRAP/acp5), cathepsin K (ctsk), osteoclast-associated receptor (oscar), and calcitonin receptor (calcr) (6).The liver X receptors, LXR␣ and LXR␤, are me...

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“…The dendritic cell-specific transmembrane protein (DC-STAMP), a seven-transmembrane protein, was first identified as a protein responsible for the fusion of preosteoclasts. 20,21 No multinucleated osteoclasts were observed, but many preosteoclasts were detected in DC-STAMP À / À mice. The bone-resorbing activity of DC-STAMP À / À preosteoclasts was lower than that in multinucleated osteoclasts.…”

Section: Structure and Function Of Osteoclastsmentioning

confidence: 99%

Vitamin D endocrine system and osteoclasts

Takahashi¹,

Udagawa²,

Suda³

2014

BoneKEy Reports

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Vitamin D was discovered as an anti-rachitic agent preventing a failure in bone mineralization, but it is now established that the active form of vitamin D 3 (1a,25(OH) 2 D 3 ) induces bone resorption. Discovery of the receptor activator of nuclear factor -kB ligand (RANKL) uncovered the molecular mechanism by which 1a,25(OH) 2 D 3 stimulates bone resorption. Treating osteoblastic cells with 1a,25(OH) 2 D 3 stimulates RANKL expression, which in turn induces osteoclastogenesis. Nevertheless, active vitamin D compounds such as calcitriol (1a,25(OH) 2 D 3 ), alfacalcidol (1a(OH)D 3 ) and eldecalcitol (1a,25-dihydroxy-2b-(3-hydroxypropoxy) vitamin D 3 ) have been used as therapeutic drugs for osteoporosis, as they increase bone mineral density (BMD) in osteoporotic patients. Paradoxically, the increase in BMD is caused by the suppression of bone resorption. Several studies have been performed to elucidate the mechanism by which active vitamin D compounds suppress bone resorption in vivo. Our study showed that daily administration of eldecalcitol to mice suppressed neither the number of osteoclast precursors in the bone marrow nor the number of osteoclasts formed in ex vivo cultures. Eldecalcitol administration suppressed RANKL expression in osteoblasts. This review discusses how the difference between in vitro and in vivo effects of active vitamin D compounds on bone resorption is induced.

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RANKL-induced DC-STAMP Is Essential for Osteoclastogenesis

Cited by 337 publications

References 24 publications

Osteoclast stimulatory transmembrane protein and dendritic cell–specific transmembrane protein cooperatively modulate cell–cell fusion to form osteoclasts and foreign body giant cells

Osteoclast stimulatory transmembrane protein and dendritic cell–specific transmembrane protein cooperatively modulate cell–cell fusion to form osteoclasts and foreign body giant cells

Activation of Liver X Receptor (LXR) Inhibits Receptor Activator of Nuclear Factor κB Ligand (RANKL)-induced Osteoclast Differentiation in an LXRβ-dependent Mechanism

Vitamin D endocrine system and osteoclasts

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