PKC‐ζ expression is lower in osteoblasts from arthritic patients: IL1‐β and TNF‐α induce a similar decrease in non‐arthritic human osteoblasts

Zini, Nicoletta; Bavelloni, Alberto; Lisignoli, Gina; Ghisu, Sonia; Valmori, Aurelio; Martelli, Alberto M.; Facchini, Andrea; Maraldi, Nadir M.

doi:10.1002/jcb.21424

Cited by 8 publications

(6 citation statements)

References 40 publications

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“…Osteoblasts from arthritic patients had reduced expression of PKCζ due to induction of IL-1β or TNF-α, suggesting that the stress stimuli which lead to decreased bone mineral density could be functioning in part through this mechanism. (34) Our findings suggest that under normal differentiation conditions PKCζ may be utilized to activate AKT signaling through coordinated IGF-I receptor/RPTPβ activation and that cytokines which downregulate this enzyme could inhibit osteoblast differentiation through this mechanism.…”

Section: Discussionmentioning

confidence: 73%

IRS-1 Functions as a Molecular Scaffold to Coordinate IGF-I/IGFBP-2 Signaling During Osteoblast Differentiation

Shen

Rosen

et al. 2016

Journal of Bone and Mineral Research

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Insulin like growth factor I (IGF-I) and insulin like growth factor binding protein-2 (IGFBP-2) function coordinately to stimulate AKT and osteoblast differentiation. IGFBP-2 binding to receptor protein tyrosine phosphatase β (RPTPβ) stimulates polymerization and inactivation of phosphatase activity. Because phosphatase and tensin homolog (PTEN) is the primary target of RPTPβ, this leads to enhanced PTEN tyrosine phosphorylation and inactivation. However RPTPβ inactivation also requires IGF-I receptor activation. The current studies were undertaken to determine the mechanism by which IGF-I mediates changes in RPTPβ function in osteoblasts. IGFBP-2/IGF-I stimulated vimentin binding to RPTPβ and this was required for RPTPβ polymerization. Vimentin serine phosphorylation mediated its binding to RPTPβ and PKCζ was identified as the kinase that phosphorylated vimentin. To determine the mechanism underlying IGF-I stimulation of PKCζ-mediated vimentin phosphorylation, we focused on insulin receptor substrate–1 (IRS-1). IGF-I stimulated IRS-1 phosphorylation and recruitment of PKCζ and vimentin to phospho-IRS-1. IRS-1 immunoprecipitates containing PKCζ and vimentin were used to confirm that activated PKCζ directly phosphorylated vimentin. PKCζ does not contain a SH-2 domain that is required to bind to phospho-IRS-1. To determine the mechanism of PKCζ recruitment we analyzed the role of p62 (a PKCζ binding protein) that contains a SH2 domain. Exposure to differentiation medium plus IGF-I stimulated PKCζ/p62 association. Subsequent analysis showed the p62/PKCζ complex was co-recruited to IRS-1. Peptides that disrupted p62/PKCζ or p62/IRS-1 inhibited IGF-I/IGFBP-2 stimulated PKCζ activation, vimentin phosphorylation, PTEN tyrosine phosphorylation, AKT activation, and osteoblast differentiation. The importance of these signaling events for differentiation was confirmed in primary mouse calvarial osteoblasts. These results demonstrate the cooperative interaction between RPTPβ and the IGF-I receptor leading to a coordinated series of signaling events that are required for osteoblast differentiation. Our findings emphasize the important role IRS-1 plays in modulating these signaling events and confirm its essential role in facilitating osteoblast differentiation.

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Section: Discussionmentioning

confidence: 73%

IRS-1 Functions as a Molecular Scaffold to Coordinate IGF-I/IGFBP-2 Signaling During Osteoblast Differentiation

Shen

Rosen

et al. 2016

Journal of Bone and Mineral Research

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“…Akt is an important downstream effector of signaling through phosphoinositide 3-kinase, and through the conventional PKCa/b and novel PKCd isoforms, that we had previously found equally expressed in OA and RA osteoblasts (Zini et al, 2008). Akt phosphorylation was induced only in CCL20-activated RA osteoblasts and was associated with a significant increase in their proliferation.…”

Section: Discussionmentioning

confidence: 96%

CCL20/CCR6 chemokine/receptor expression in bone tissue from osteoarthritis and rheumatoid arthritis patients: Different response of osteoblasts in the two groups

Lisignoli

Manferdini

Codeluppi

et al. 2009

Journal Cellular Physiology

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Subchondral bone remodeling in osteoarthritis (OA) and rheumatoid arthritis (RA) is mainly characterized by the formation of osteophytes/fibrosis and by the presence of infiltrating cells associated to bone resorption. In this study we analyzed CC (cysteine cysteine motif) chemokine ligand (CCL)20 and CC chemokine receptor (CCR)6 function in subchondral bone tissue and osteoblasts isolated from OA and RA patients. CCL20/CCR6 expression was evaluated by immunohistochemical techniques in bone tissue from OA and RA patients. CCL20-functional tests were performed on osteoblasts isolated from OA and RA patients to evaluate enzymatic response and cell proliferation. Moreover, we assessed Akt phosphorylation as the major signaling pathway for CCL20. In bone tissue biopsies we found that osteoblasts from both OA and RA patients expressed CCR6 while CCL20 was expressed only by RA osteoblasts. Both CCR6 and CCL20 were highly expressed in osteocytes and mononuclear cells from only RA patients. CCL20-stimulated OA osteoblasts showed a significant increase in beta-N-acetylhexosaminidase release compared to RA. Conversely, a significant increase in cellular proliferation was found only in CCL20-stimulated RA osteoblasts associated to Akt phosphorylation. These data were confirmed in bone tissue biopsies. This study demonstrates a different expression of CCL20-positive osteoblasts in OA versus RA disease that seem to be associated with the presence of infiltrating mononuclear cells. Moreover, CCL20 stimulation resulted in a greater proliferative response in RA osteoblasts compared to OA osteoblasts, mediated by Akt signaling, while OA osteoblasts showed increased enzymatic activity, thus suggesting a differential role of this chemokine in OA and RA.

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“…There is scarce evidence available regarding inflammation‐associated changes in expression of PKC isozymes in smooth muscle cells during pathological conditions. Interestingly, a redistribution of PKC isoform expression has been observed for arthritic osteoblasts 38 . Proinflammatory T H 1 cytokines, such as IL‐1β and TNF‐α, elicited decreased PKCζ isoform expression.…”

Section: Discussionmentioning

confidence: 98%

“…Interestingly, a redistribution of PKC isoform expression has been observed for arthritic osteoblasts. 38 Proinflammatory T H 1 cytokines, such as IL-1b and TNF-a, elicited decreased PKCf isoform expression. In contrast, no changes in PKC isoform expression were identified, suggesting that its modulation might not depend on proinflammatory cytokines, such as IL-1b and TNF-a.…”

Section: Discussionmentioning

confidence: 99%

The contribution of protein kinase C and CPI‐17 signaling pathways to hypercontractility in murine experimental colitis

Ihara

Chappellaz

Turner

et al. 2011

Neurogastroenterology Motil

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The outcomes suggest that both conventional and novel PKC isozymes contribute to the phasic and tonic contractile components of BALB/c colonic circular smooth muscle under normal conditions, with novel PKC isozymes having a greater contribution to the tonic contraction. However, no effect of inflammation was observed on the relative contribution of PKC and CPI-17 toward the observed hypercontractility.

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PKC‐ζ expression is lower in osteoblasts from arthritic patients: IL1‐β and TNF‐α induce a similar decrease in non‐arthritic human osteoblasts

Cited by 8 publications

References 40 publications

IRS-1 Functions as a Molecular Scaffold to Coordinate IGF-I/IGFBP-2 Signaling During Osteoblast Differentiation

IRS-1 Functions as a Molecular Scaffold to Coordinate IGF-I/IGFBP-2 Signaling During Osteoblast Differentiation

CCL20/CCR6 chemokine/receptor expression in bone tissue from osteoarthritis and rheumatoid arthritis patients: Different response of osteoblasts in the two groups

The contribution of protein kinase C and CPI‐17 signaling pathways to hypercontractility in murine experimental colitis

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