Pin1 Regulates Osteoclast Fusion Through Suppression of the Master Regulator of Cell Fusion DC‐STAMP

Islam, Rabia; Bae, Han Sol; Yoon, Won‐Joon; Woo, Kyung Mi; Baek, Jong‐Min; Kim, Hong Hee; Uchida, Takafumi; Ryoo, Hyun‐Mo

doi:10.1002/jcp.24679

Cited by 34 publications

(54 citation statements)

References 61 publications

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“…It was recently reported that Pin1 -/-mice exhibit a defect in bone morphogenetic protein signaling in osteoblasts but normal osteoclast function (Shen et al 2013). However, Islam et al (2014) demonstrated wide variation in the sizes of osteoclasts in Pin1 -/-mice, with very high numbers of large osteoclasts. Since Pin1 -/-mice show significant bone loss with aging ), we examined whether PIN1 is involved in osteoclast differentiation as well as up-regulation of osteoclastogenic cytokine expression in BMMs (the culmination of this process is periodontal bone destruction).…”

Section: Discussionmentioning

confidence: 93%

PIN1 Inhibition Suppresses Osteoclast Differentiation and Inflammatory Responses

et al. 2014

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Inflammatory responses and osteoclast differentiation play pivotal roles in the pathogenesis of osteolytic bone diseases such as periodontitis. Although overexpression or inhibition of peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1) offers a possible therapeutic strategy for chronic inflammatory diseases, the role of PIN1 in periodontal disease is unclear. The aim of the present study was to evaluate PIN1 expression in periodontitis patients as well as the effects of PIN1 inhibition by juglone or PIN1 small-interfering RNA (siRNA) and of PIN1 overexpression using a recombinant adenovirus encoding PIN1 (Ad-PIN1) on the inflammatory response and osteoclastic differentiation in lipopolysaccharide (LPS)-and nicotine-stimulated human periodontal ligament cells (PDLCs). PIN1 was up-regulated in chronically inflamed PDLCs from periodontitis patients and in LPS-and nicotine-exposed PDLCs. Inhibition of PIN1 by juglone or knockdown of PIN1 gene expression by siRNA markedly attenuated LPS-and nicotine-stimulated prostaglandin E 2 (PGE 2 ) and nitric oxide (NO) production, as well as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, whereas PIN1 overexpression by Ad-PIN1 increased it. LPS-and nicotine-induced nuclear factor (NF)-κB activation was blocked by juglone and PIN1 siRNA but increased by Ad-PIN1. Conditioned medium prepared from LPS-and nicotinetreated PDLCs increased the number of tartrate-resistant acid phosphatase-stained osteoclasts and osteoclast-specific gene expression. These responses were blocked by PIN1 inhibition and silencing but stimulated by Ad-PIN1. Furthermore, juglone and PIN1 siRNA inhibited LPS-and nicotine-induced osteoclastogenic cytokine expression in PDLCs. This study is the first to demonstrate that PIN1 inhibition exhibits anti-inflammatory effects and blocks osteoclastic differentiation in LPS-and nicotine-treated PDLCs. PIN1 inhibition may be a therapeutic strategy for inflammatory osteolysis in periodontal disease.

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Section: Discussionmentioning

confidence: 93%

PIN1 Inhibition Suppresses Osteoclast Differentiation and Inflammatory Responses

et al. 2014

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“…Pin1 KO mice were generated from heterozygous matings as described previously (28). All animal studies were reviewed and approved by the Special Committee on Animal Welfare, Seoul National University, Seoul, Republic of Korea.…”

Section: Methodsmentioning

confidence: 99%

“…Extraction of Total RNAs, RT-PCR, and Real-time PCR (Quantitative PCR)-Total RNA extraction from cultured cells, RT-PCR, quantitative PCR, and the primer sets for real-time PCR have been described previously (25,28).…”

Section: Methodsmentioning

confidence: 99%

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Pin1-mediated Modification Prolongs the Nuclear Retention of β-Catenin in Wnt3a-induced Osteoblast Differentiation

Shin¹,

Islam²,

Yoon³

et al. 2016

Journal of Biological Chemistry

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The canonical Wnt signaling pathway, in which ␤-catenin nuclear localization is a crucial step, plays an important role in osteoblast differentiation. Pin1, a prolyl isomerase, is also known as a key enzyme in osteogenesis. However, the role of Pin1 in canonical Wnt signal-induced osteoblast differentiation is poorly understood. We found that Pin1 deficiency caused osteopenia and reduction of ␤-catenin in bone lining cells. Similarly, Pin1 knockdown or treatment with Pin1 inhibitors strongly decreased the nuclear ␤-catenin level, TOP flash activity, and expression of bone marker genes induced by canonical Wnt activation and vice versa in Pin1 overexpression. Pin1 interacts directly with and isomerizes ␤-catenin in the nucleus. The isomerized ␤-catenin could not bind to nuclear adenomatous polyposis coli, which drives ␤-catenin out of the nucleus for proteasomal degradation, which consequently increases the retention of ␤-catenin in the nucleus and might explain the decrease of ␤-catenin ubiquitination. These results indicate that Pin1 could be a critical target to modulate ␤-catenin-mediated osteogenesis.

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“…The most prominent of these is DC‐STAMP (dendritic cell‐specific transmembrane protein) (Kukita et al, 2004; Yagi et al, 2005; Iwasaki et al, 2008; Mensah et al, 2010; Chiu et al, 2012; Chiu and Ritchlin, 2016), which has been identified as one of the most essential single factors supporting both differentiation and fusion. However, also other factors such as CD47 (Han et al, 2000; Lundberg et al, 2007; Maile et al, 2011; Koskinen et al, 2013; Hobolt‐Pedersen et al, 2014), syncytin‐1 (Soe et al, 2011), OC‐STAMP (osteoclast stimulatory transmembrane protein) (Miyamoto et al, 2012; Witwicka et al, 2015), dynamin (Shin et al, 2014; Verma et al, 2014), Pin1 (peptidyl‐prolyl cis‐trans isomerase NIMA‐interacting 1) (Islam et al, 2014; Cho et al, 2015), and e‐cadherin (Mbalaviele et al, 1995; Fiorino and Harrison, 2016) are involved in OC fusion, but it is important to stress that this list is not exhaustive. In order to identify the role of these factors , a series of molecular techniques, and cellular model systems have been employed, which in general are evaluated through end‐point measurements by counting the number of multi‐nucleated OCs, number of nuclei per OC, resorptive activity, and so forth at the end of the incubation period.…”

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confidence: 99%

Osteoclast Fusion: Time‐Lapse Reveals Involvement of CD47 and Syncytin‐1 at Different Stages of Nuclearity

Møller

Delaissé

Søe

2016

Journal Cellular Physiology

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Investigations addressing the molecular keys of osteoclast fusion are primarily based on end‐point analyses. No matter if investigations are performed in vivo or in vitro the impact of a given factor is predominantly analyzed by counting the number of multi‐nucleated cells, the number of nuclei per multinucleated cell or TRAcP activity. But end‐point analyses do not show how the fusion came about. This would not be a problem if fusion of osteoclasts was a random process and occurred by the same molecular mechanism from beginning to end. However, we and others have in the recent period published data suggesting that fusion partners may specifically select each other and that heterogeneity between the partners seems to play a role. Therefore, we set out to directly test the hypothesis that fusion factors have a heterogenic involvement at different stages of nuclearity. Therefore, we have analyzed individual fusion events using time‐lapse and antagonists of CD47 and syncytin‐1. All time‐lapse recordings have been studied by two independent observers. A total of 1808 fusion events were analyzed. The present study shows that CD47 and syncytin‐1 have different roles in osteoclast fusion depending on the nuclearity of fusion partners. While CD47 promotes cell fusions involving mono‐nucleated pre‐osteoclasts, syncytin‐1 promotes fusion of two multi‐nucleated osteoclasts, but also reduces the number of fusions between mono‐nucleated pre‐osteoclasts. Furthermore, CD47 seems to mediate fusion mostly through broad contact surfaces between the partners’ cell membrane while syncytin‐1 mediate fusion through phagocytic‐cup like structure. J. Cell. Physiol. 232: 1396–1403, 2017. © 2016 Wiley Periodicals, Inc.

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Pin1 Regulates Osteoclast Fusion Through Suppression of the Master Regulator of Cell Fusion DC‐STAMP

Cited by 34 publications

References 61 publications

PIN1 Inhibition Suppresses Osteoclast Differentiation and Inflammatory Responses

PIN1 Inhibition Suppresses Osteoclast Differentiation and Inflammatory Responses

Pin1-mediated Modification Prolongs the Nuclear Retention of β-Catenin in Wnt3a-induced Osteoblast Differentiation

Osteoclast Fusion: Time‐Lapse Reveals Involvement of CD47 and Syncytin‐1 at Different Stages of Nuclearity

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