Macrophage colony-stimulating factor is indispensable for both proliferation and differentiation of osteoclast progenitors.

Tanaka, Sakae; Takahashi, Naoyuki; Udagawa, Nobuyuki; Tamura, Tatsuya; Akatsu, Takuhiko; Stanley, E. Richard; Kurokawa, Takahide; Suda, Toshio

doi:10.1172/jci116179

Cited by 526 publications

(357 citation statements)

References 30 publications

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“…Clinical scores for the mice were determined for each of the four paws on study days [16][17][18][19][20][21][22][23][24][25][26][27][28]. The scores for all the four paws were given using the following criteria: 0, normal joints; 1, swelling in one digit or joint or minimal diffuse erythema; 2, swelling in two digits or joints or mild diffuse erythema; 3, swelling in three digits or joints or moderate diffuse erythema; 4, swelling in four digits or joints or marked diffuse erythema; 5, severe diffuse erythema and severe swelling of the entire paw and rigid joints.…”

Section: Collagen-induced Arthritismentioning

confidence: 99%

“…Elevated levels of its ligand M-CSF are observed in the joints of RA patients, contributing to the development of macrophages and osteoclasts, which are the mediators of bone erosion (21)(22)(23)(24). Blockade of the M-CSF-c-Fms axis has been shown to inhibit the progression of arthritis in animal models indicating that it may play a pivotal role in the pathogenesis of RA (25,26).…”

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confidence: 99%

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SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Madan¹,

Goh²,

Hart³

et al. 2012

The Journal of Immunology

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SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases.

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Section: Collagen-induced Arthritismentioning

confidence: 99%

mentioning

confidence: 99%

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Madan¹,

Goh²,

Hart³

et al. 2012

The Journal of Immunology

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“…17 In the cell contact wells, BMCs (1310 6 /well) and different numbers of activated Treg cells (2310 4 -2310 5 cells/well) were cocultured in 24-well plates for either 7 or 10 days in the presence of M-CSF (50 ng/ml) and RANKL (50 ng/ ml). In the no-contact transwell cocultures, the osteoclast precursors were loaded into the lower chambers and Treg cells were loaded into the upper chambers.…”

Section: Modulation Of Treg Cells On Osteoclast Functionsmentioning

confidence: 99%

“…3 OCs are multinucleated cells that are derived from hematopoietic precursors of the monocyte/macrophage lineage in the presence of macrophage colony-stimulating factor (M-CSF) and RANKL. [4][5][6][7] Many other cytokines have been shown to affect bone metabolism and OC activity, including interleukin (IL)-1, IL-4, IL-7, IL-10, IL-13 and TNF. [8][9][10] A previous study by our lab showed that both transforming growth factor-beta 1 (TGF-b1) and IL-10 suppress osteoclastogenesis and bone resorption in a dosage-dependent manner and exhibit synergistic effects.…”

Section: Introductionmentioning

confidence: 99%

Estrogen enhances the functions of CD4+CD25+Foxp3+ regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro

et al. 2010

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Cross-talk has been shown to occur between the immune system and bone metabolism pathways. In the present study, we investigated the impact of CD4 1 CD25 1 Foxp3 1 regulatory T (Treg) cells on osteoclastogenesis and bone resorption. Treg cells that were isolated and purified from peripheral blood mononuclear cells (PBMCs) of healthy adults inhibited both the differentiation of osteoclasts (OCs) from human embryo bone marrow cells (BMCs) and the pit formation in a dose-dependent manner. In cell cocultures, the production levels of both interleukin-10 (IL-10) and transforming growth factor-beta 1 (TGF-b1) were proportionally upregulated as the ratio of Treg cells to BMCs was increased, and the inhibition of OC differentiation and bone resorption by Treg cells was completely reversed by anti-IL-10 and anti-TGF-b1 antibodies. Treatment of BMC and Treg cell cocultures with 17b-estradiol (E2) at concentrations between 10 27 and 10 29 mol/l suppressed OC differentiation and bone resorption more efficiently than it did in cultures of BMCs alone; this enhanced suppression occurred via the stimulation of Treg cell IL-10 and TGF-b1 expression. These data suggest that Treg cells suppress OC differentiation and bone resorption by secreting IL-10 and TGF-b1. E2 enhances the suppressive effects of Treg cells on OC differentiation and bone resorption by stimulating IL-10 and TGF-b1 secretion from these cells. Therefore, Treg cell-derived IL-10 and TGF-b1 are likely involved in the regulation of E2 on bone metabolism and represent potential therapeutic targets for the treatment of postmenopausal osteoporosis (PMO).

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“…3 The precursors of Ocs are the monocyte/macrophage lineage of hematopoietic cells, of which proliferation and survival are dependent on macrophage colony-stimulating factor (M-CSF). 4 Thus, bone marrow-derived monocytes/ macrophages (BMMs) generate functional Ocs, when cultured in the presence of RANKL and M-CSF in vitro. The macrophage cell line RAW264 or RAW264.7, when cultured with RANKL, can also differentiate to the Oc with boneresorbing capability.…”

Section: Introductionmentioning

confidence: 99%

Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-κB transactivation by RANKL

et al. 2006

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Osteoclast (Oc) differentiation is fundamentally controlled by receptor activator of nuclear factor kappaB ligand (RANKL). RANKL signalling targets include mitogen-activated protein kinases (MAPKs), nuclear factor kappaB (NF-jB), and nuclear factor of activated T cells (NFAT)c1. In this study, we found that p38 MAPK upstream components transforming growth factor-beta-activated kinase 1 (TAK1), MKK3, and MKK6 increased by RANKL in an early stage of osteoclastogenesis from primary bone marrow cells, which led to enhanced p38 activation. Retroviral transduction of dominant-negative (DN) forms of TAK1 and MKK6, but not that of MKK3, reduced Oc differentiation. Transduction of TAK1-DN and MKK6-DN and treatment with the p38 inhibitor SB203580 attenuated NFATc1 induction by RANKL. TAK1-DN, MKK6-DN, and SB203580, but not MKK3-DN, also suppressed RANKL stimulation of NF-jB transcription activity in a manner dependent on p65 phosphorylation on Ser-536. These results indicate that TAK1 and MKK6 constitute the p38 signalling pathway to participate to Oc differentiation by RANKL through p65 phosphorylation and NFATc1 induction, and that MKK6 and MKK3 have differential roles in osteoclastogenesis from bone marrow precursors.

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Macrophage colony-stimulating factor is indispensable for both proliferation and differentiation of osteoclast progenitors.

Abstract: The mechanism of action of macrophage colony-stimulating factor (M-CSF) in osteoclast development was examined in a co-culture system of mouse osteoblastic cells and spleen cells.

Cited by 526 publications

References 30 publications

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Estrogen enhances the functions of CD4+CD25+Foxp3+ regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro

Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-κB transactivation by RANKL

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