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

Huang, Hao; Ryu, Jae‐Chun; J, Ha; Ej, Chang; Kim, Hyung Jun; Kitamura, Toshio; Zh, Lee

doi:10.1038/sj.cdd.4401882

Cited by 131 publications

(120 citation statements)

References 44 publications

(77 reference statements)

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“…45 MKK3 and MKK6 have been found to be required for osteoclastogenesis in vitro. 37,46,50 In accordance with this, both Mkk3 À / À and Mkk6 À / À mice exhibit a higher trabecular bone mass with increased trabecular number and decreased trabecular spacing in comparison with control littermates at 4 months of age. 37 In those mice, osteoclast number is reduced, whereas bone formation is normal.…”

Section: The P38 Mapk Signaling Pathway In Osteoclastssupporting

confidence: 53%

“…37 In addition, Mkk3 À / À and Mkk6 À / À mice are partially protected against bone loss induced by estrogen deficiency due to diminished bone resorption. 37 Absence of MKK3 37 or MKK6 46,50 in primary bone marrow cell cultures stimulated by M-CSF and RANKL results in reduced p38 MAPK activation, decreased expressions of Nfatc1 and other osteoclast marker genes (cathepsin K (CtsK), Oscar and matrix metalloproteinase 9) and impaired bone resorption.…”

Section: The P38 Mapk Signaling Pathway In Osteoclastsmentioning

confidence: 99%

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Focus on the p38 MAPK signaling pathway in bone development and maintenance

2015

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The p38 mitogen-activated protein kinase (MAPK) signaling pathway can be activated in response to a wide range of extracellular signals. As a consequence, it can generate many different biological effects that depend on the stimulus and on the activated cell type. Therefore, this pathway has been found to regulate many aspects of tissue development and homeostasis. Recent work with the aid of genetically modified mice has highlighted the physiological functions of this pathway in skeletogenesis and postnatal bone maintenance. In this review, emphasis is given to the roles of the p38 MAPK pathway in chondrocyte, osteoblast and osteoclast biology. In particular, we describe the molecular mechanisms of p38 MAPK activation and downstream targets. The requirement of this pathway in physiological bone development and homeostasis is demonstrated by the ability of p38 MAPK to regulate master transcription factors controlling geneses and functions of chondrocytes, osteoblasts and osteoclasts.

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Section: The P38 Mapk Signaling Pathway In Osteoclastssupporting

confidence: 53%

Section: The P38 Mapk Signaling Pathway In Osteoclastsmentioning

confidence: 99%

Focus on the p38 MAPK signaling pathway in bone development and maintenance

2015

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“…RANKL-induced osteoclast differentiation requires TAK1 for NF-κB activation [25]. Herefore, we determined whether DPCPX affects the recruitment, and interaction of TAK1 with TRAF6 by RANKL.…”

Section: A 1 R Blockade Suppresses Osteoclastogenesis and Bone-resorbmentioning

confidence: 99%

“…A 1 R blockade disrupts RANKL-induced formation of TRAF6-TAK1 complex in primary BMMs TAK1, a MAPK kinase kinase can form complexes with RANK and TRAF6, and was up-regulated in RANKLinduced osteoclastogenesis ( [23][24][25]. RANKL-induced osteoclast differentiation requires TAK1 for NF-κB activation [25].…”

Section: A 1 R Blockade Suppresses Osteoclastogenesis and Bone-resorbmentioning

confidence: 99%

“…Another signaling protein, transformation growth factor-β (TGF-β) activated kinase-1 (TAK1) has been implicated in RANKL-induced osteoclastogenesis [23][24][25]. Upon RANK receptor engagement, the cytoplasmic domain of RANK interacts with an adaptor protein, tumor necrosis factor-receptorassociated factor 6 (TRAF6), and endogenous TAK1 is recruited to the TRAF6 complex.…”

Section: Introductionmentioning

confidence: 99%

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Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling

Cronstein

2012

Purinergic Signalling

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Adenosine is an endogenous nucleoside that modulates many physiological processes through four receptor subtypes (A 1 , A 2a , A 2b , A 3 ). Previous work from our laboratory has uncovered a critical role for adenosine A 1 receptor (A 1 R) in osteoclastogenesis both in vivo and in vitro. Our current work focuses on understanding the details of how A 1 R modulates the receptor activator of NF-κB ligand (RANKL)-induced signaling in osteoclastogenesis. Osteoclasts were generated from mouse bone marrow precursors in the presence of RANKL and macrophage-colony stimulating factor. A pharmacological antagonist of A 1 R (DPCPX) inhibited RANKL-induced osteoclast differentiation, including osteoclast-specific genes (Acp5, MMP9, β 3 Integrin, α v Integrin, and CTSK) and osteoclast-specific transcription factors such as c-fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) expression in a dose-dependent manner. DPCPX also inhibited RANKL-induced activation of NF-κB and JNK/ c-Jun but had little effect on other mitogen-activated protein kinases (p38 and Erk). Finally, immunoprecipitation analysis showed that blockade of A 1 R resulted in disruption of the association of tumor necrosis factor receptor-associated factor 6 (TRAF6) and transforming growth factor-β-activated kinase 1 (TAK1), a signaling event that is important for activation of NF-κB and JNK, suggesting the participation of adenosine/ A 1 R in early signaling of RANKL. Collectively, these data demonstrated an important role of adenosine, through A 1 R in RANKL-induced osteoclastogenesis.

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Decreased collagen‐induced arthritis severity and adaptive immunity in MKK‐6–deficient mice

Hammaker

Topolewski

Edgar

et al. 2012

Arthritis & Rheumatism

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Objective MAPK kinases MKK3 and MKK6 regulate p38 MAPK activation in inflammatory diseases such as rheumatoid arthritis. Previous studies demonstrated that MKK3- or MKK6-deficiency inhibits K/BxN serum-induced arthritis. However, the role of these kinases in adaptive immunity-dependent models of chronic arthritis is not known. The goal of this study was to evaluate MKK3- and MKK6-deficiency in the collagen induced arthritis model. Methods Wildtype, MKK3−/−, and MKK6−/− mice were immunized with bovine type II collagen (CII). Disease activity was evaluated by semiquantitative scoring, histology, and microcomputed tomography. Serum anti-collagen antibody levels were quantified by ELISA. In-vitro T cell cytokine response was measured by flow cytometry and multiplex analysis. Expression of joint cytokines and matrix metalloproteinase was determined by qPCR. Results MKK6-deficiency markedly reduced arthritis severity compared with WT mice, while absence of MKK3 had an intermediate effect. Joint damage was minimal in arthritic MKK6−/− mice and intermediate in MKK3−/− mice compared with wild type mice. MKK6−/− mice had modestly lower levels of pathogenic anti-collagen antibodies than WT or MKK3−/− mice. In vitro T cell assays showed reduced proliferation and IL-17 production by MKK6−/− cells in response to type II collagen. Gene expression of synovial IL-6, matrix metalloproteinases MMP3, and MMP13 was significantly inhibited in MKK6-deficient mice. Conclusion Reduced disease severity in MKK6−/− mice correlated with decreased anti-collagen responses indicating that MKK6 is a crucial regulator of inflammation joint destruction in CIA. MKK6 is a potential therapeutic target in complex diseases involving adaptive immune responses like rheumatoid arthritis.

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

Cited by 131 publications

References 44 publications

Focus on the p38 MAPK signaling pathway in bone development and maintenance

Focus on the p38 MAPK signaling pathway in bone development and maintenance

Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling

Decreased collagen‐induced arthritis severity and adaptive immunity in MKK‐6–deficient mice

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