PIN1 Inhibition Suppresses Osteoclast Differentiation and Inflammatory Responses

Abstract

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.

Juglone ameliorates skin wound healing by promoting skin cell migration through Rac1/Cdc42/PAK pathway

“…Phosphorylation of many mitosis‐regulating proteases such as PLK‐11, Cdc25, and Cdc27 depends on Pin1 . Hence, modulation of Pin1 is reported in many processes and diseases ranging from inflammation and differentiation to vascular dysfunction and skin, breast, liver, and prostate cancers . In the present study therefore, we used juglone, an established Pin1 inhibitor, to check if it has any effect on an important process of wound healing in vitro and/or in vivo.…”

“…Juglone, a natural compound found in walnuts, is a peptidyl‐prolyl cis/trans isomerase Protein Never in Mitosis Gene A Interacting‐1 (Pin1) inhibitor that was once assumed toxic to human cells . It is now known that juglone possesses anticancer, antiproliferative, antimicrobial, anti‐inflammatory, and anti‐aging capabilities . Walnuts have been used for hair dying and protecting against Alzheimer's disease and have been associated with anti‐inflammatory, anti‐oxidative, and antihemolytic activities .…”

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

“…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.…”

Expression of Phospholipase D in Periodontitis and Its Role in the Inflammatory and Osteoclastic Response by Nicotine‐ and Lipopolysaccharide‐Stimulated Human Periodontal Ligament Cells

“…PDL cells treated with both nicotine and LPS are an in vitro model used to recapitulate the effects of periodontitis in smokers with poor oral hygiene 8 . The combination of nicotine and LPS stimulates the formation of osteoclast‐like cells by increasing macrophage colony‐stimulating factor (M‐CSF) and PGE 2 production in osteoblasts 9 and increases PGE 2 and cyclooxygenase‐2 (COX‐2) expression in osteoblasts 10 .…”