The phosphatidylinositol 3-Kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation

Lee, S.E.; Woo, Kyung Mi; Kim, S.Y.; Kim, H.-M.; Kwack, KyuBum; Lee, Z.H.; Kim, H.-H.

doi:10.1016/s8756-3282(01)00657-3

Cited by 280 publications

(218 citation statements)

References 36 publications

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“…Studies with pharmacological inhibitors and genedeficient mice provided evidence that the activity of p38 and JNK1 is required for osteoclastogenesis. 10,11,13 In this context, the activation of p38 and JNK were detected during osteoclastogenesis (Figure 1b). The p38 and JNK activity was highest 1 day after RANKL treatment and reduced as cells become mature (Figure 1b).…”

Section: Resultsmentioning

confidence: 86%

“…11,12 To investigate whether the increase in TAK1 protein level can consequently cause an enhanced p38 activation, we incubated the Oc precursor cells with RANKL or vehicle for 1 day, deprived of serum and RANKL for 5 h, and re-stimulated with RANKL or TNFa for 15 min. TNFa, in the absence of RANKL, can stimulate Oc generation from RANKL-primed cells.…”

Section: Resultsmentioning

confidence: 99%

“…10 The involvement of p38 in osteoclastogenesis has been demonstrated by the treatment of bone marrow precursor cells with pharmacological inhibitors of the kinase. [11][12][13] The expression of dominant-negative (DN) form of p38a into RAW264 cells partially inhibited RANKL-induced osteoclastic differentiation of these cells. 13 Interestingly, the activation of p38 MAPK by RANKL was observed in bone marrow precursor cells but not in fully differentiated Ocs.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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“…(21)(22)(23) However, the in vivo data indicated a normal number of osteoclasts in Pik3r1 DOc/À Pik3r2 À/À mice, and the formation of TRAP-positive osteoclasts from Pik3r1 DOc/À Pik3r2 À/À cells was comparable to control cells in vitro. Our results suggest that class IA PI3K is dispensable for the differentiation and survival of osteoclasts, and indicate that other PI3Ks sensitive to the PI3K inhibitors evidently play a redundant role.…”

Section: Discussionmentioning

confidence: 86%

“…(14,15) PI3K is known to be stimulated by M-CSF and integrin a v b 3 , both of which are crucial for osteoclast function. (8,9) In vitro inhibitor experiments suggest that PI3K is involved in the differentiation (21) and the bone-resorbing activity (22,23) of osteoclasts, but the level of PI-3,4,5-P 3 has not been quantitated in osteoclasts, and the in vivo function of PI3K in osteoclasts has also not been elucidated. In addition, because the PI3K inhibitors such as wortmannin and LY294002 suppress the catalytic activity of all classes of the PI3Ks, (16,24) the role of each PI3K class needs to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

Shirakawa

Nakamura

Masuda

et al. 2012

Journal of Bone and Mineral Research

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Class IA phosphatidylinositol 3-kinases (PI3Ks) are activated by growth factor receptors and regulate a wide range of cellular processes. In osteoclasts, they are activated downstream of a v b 3 integrin and colony-stimulating factor-1 receptor (c-Fms), which are involved in the regulation of bone-resorbing activity. The physiological relevance of the in vitro studies using PI3K inhibitors has been of limited value, because they inhibit all classes of PI3K. Here, we show that the osteoclast-specific deletion of the p85 genes encoding the regulatory subunit of the class IA PI3K results in an osteopetrotic phenotype caused by a defect in the bone-resorbing activity of osteoclasts. Class IA PI3K is required for the ruffled border formation and vesicular transport, but not for the formation of the sealing zone. p85a/b doubly deficient osteoclasts had a defect in macrophage colony-stimulating factor (M-CSF)-induced protein kinase B (Akt) activation and the introduction of constitutively active Akt recovered the bone-resorbing activity. Thus, the class IA PI3K-Akt pathway regulates the cellular machinery crucial for osteoclastic bone resorption, and may provide a molecular basis for therapeutic strategies against bone diseases. ß

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Identification of a novel compound that inhibits osteoclastogenesis by suppressing nucleoside transporters

et al. 2016

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We screened small-molecule compounds that inhibit osteoclast differentiation to find new anti-osteoporosis agents and found that a novel compound, SUKU-1, suppressed osteoclastogenesis. We also synthesized 38 derivatives of SUKU-1 and discovered that nine of them had inhibitory effects on osteoclastogenesis and that SUKU-33 was the most potent inhibitor. Next, we investigated the mechanisms by which SUKU-33 suppressed osteoclast differentiation. By measuring the uptake of [3 H]-uridine in cells, we found that SUKU-33 suppressed both equilibrative nucleoside transporters and concentrative nucleoside transporters. These results suggest that SUKU-33 inhibits osteoclast differentiation by suppressing nucleoside transporters.

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The phosphatidylinositol 3-Kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation

Cited by 280 publications

References 36 publications

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

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

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

Identification of a novel compound that inhibits osteoclastogenesis by suppressing nucleoside transporters

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