Pro- and anti-inflammatory cytokines and osteoclastogenesis-related factors in peri-implant diseases: systematic review and meta-analysis

(2023) 23:420 Oliveira et al. BMC Oral Health https://doi.org/10.1186/s12903-023-03072-1 BMC Oral Health Open Access RESEARCH Pro‑ and anti‑inflammatory cytokines and osteoclastogenesis‑related factors in peri‑implant diseases: systematic review and meta‑analysis Jovânia Alves Oliveira1†, Roberta de Oliveira Alves2†, Isabella Mazarelo Nascimento1, Marco Antonio Rimachi Hidalgo3, Raquel Mantuaneli Scarel‑Caminaga3 and Suzane Cristina Pigossi2* Abstract Background Pro- and anti-inflammatory cytokines are acknowledged, during inflammatory bone destruction, as key regulators of osteoclast and osteoblast differentiation and activity. However, evidence regarding the exact role of pro- and anti-inflammatory cytokines and osteoclastogenesis-related factors in peri-implant diseases is unclear. We aimed to execute a systematic review and meta-analysis about the pro- and anti-inflammatory cytokines and osteo‑ clastogenesis-related factors levels in peri-implant diseases. Methods The focused question was elaborated to summarize the levels of pro-and anti-inflammatory cytokines and osteoclastogenesis-related factors in tissue samples (mRNA) and biofluids (protein levels) of patients with/with‑ out peri-implant diseases. Electronic searches of the PubMed, Cochrane Controlled Trials Registry, Web of Science, EMBASE, Scopus and Google scholar databases were conducted for publications up to March 2023. Meta-analysis evaluating the mediator´s levels (protein levels by ELISA) in peri-implant crevicular fluid (PICF) were made. The effect size was estimated and reported as the mean difference. The 95% confidence interval was estimated for each media‑ tor, and the pooled effect was determined significant if two-sided p-values < 0.05 were obtained. Results Twenty-two publications were included in the systematic review (qualitative analysis), with nine of these sub‑ jected to meta-analyses (quantitative analysis). In the qualitative analysis, higher pro-inflammatory cytokines [Inter‑ leukin (IL)-1β, IL-6] and pro-osteoclastogenic mediator [Receptor Activator of Nuclear Factor-Kappa B ligand (RANKL)] levels were observed in PICF of individuals with peri-implant diseases in comparison to healthy individuals. Higher RANKL/osteoprotegerin (OPG) ratios were observed in PICF from individuals with peri-implant diseases in comparison to healthy individuals. Meta-analysis showed higher RANKL levels in diseased groups compared to controls. Conclusions The results showed that the levels of IL-1β, IL-6, IL-10, and RANKL/OPG are not balanced in peri-implant disease, suggesting that these mediators are involved in the host osteo-immunoinflammatory response related to peri-implantitis. † Jovânia Alves Oliveira and Roberta de Oliveira Alves contributed equally to this work. *Correspondence: Suzane Cristina Pigossi Full list of author information is available at the end of the article © The Author(s) 2023. 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The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Oliveira et al. BMC Oral Health (2023) 23:420 Page 2 of 23 Keywords Peri-implantitis, Cytokines, Bone resorption, Dental implants Introduction Dental implants have been widely used to ensure the quality of life in partially and fully edentulous patients. Prospective studies with long follow-up periods showed survival rates varying from 89.5 to 99.2% [1–3]. However, peri-implant mucositis and peri-implantitis are chronic inflammatory conditions that can reduce dental implant predictability [4]. Peri-implant mucositis is a reversible condition caused by an inflammatory process restricted to peri-implant soft tissues, while peri-implantitis exhibits a progressive supporting bone loss [5]. The general prevalence of both conditions was estimated in a metaanalysis, being 42.9% for peri-implant mucositis and 21.7% for peri-implantitis [6]. The peri-implant tissue breakdown seems to be associated with a cytokine response to bacterial products, including endotoxins and lipopolysaccharides, that results in a local immunological response at the infection tissue [7, 8]. This immune reaction to infection is adjusted by the balance between pro-and anti-inflammatory cytokines that are acknowledged, during inflammatory bone destruction, as key regulators of osteoclast and osteoblast differentiation and activity [9–11]. In this context, the production of the pro-inflammatory cytokines, such as interleukin (IL)-1β, -6, and -12, interferon-gamma and tumor necrosis factor-alpha (TNF-a), in reaction to a periodontal infection, are responsible to stimulate tissue damage by activation of collagenase and other pro-inflammatory factors [12–15]. IL-1β manages the prostaglandin E2 production associated with hard tissue breakdown induction in periodontitis [16]. Higher levels of both mediators were found in the gingival crevicular fluid of patients with periodontal disease [17, 18]. Similarly, IL-6 increase T-lymphocyte proliferation and B-lymphocyte differentiation/immunoglobulin secretion as reported by in vitro studies [19, 20]. Moreover, IL-6 also induces bone resorption by itself and in conjunction with other boneresorbing mediators and acts synergistically with IL-1β. The levels of both proinflammatory cytokines in peri-implant crevicular fluid (PICF) were significantly higher in sites with peri-implantitis in comparison to healthy sites [8, 21]. Anti-inflammatory cytokines, such as IL-10, IL-4 and IL-1 receptor antagonist (IL1-RA), are produced to limit the inflammatory events, revealing protective functions during tissue destruction as reported by in vitro studies [22, 23]. IL-10 is produced by T-helper 2 cells (TH2), macrophages, and B cells and acts to reduce the production of the pro-inflammatory cytokines [24, 25]. Furthermore, IL-10 acts enhanced the B cell proliferation and differentiation and favored immunoglobulins production in vitro, balancing the immune response [26]. A previous study [27] showed that higher IL-10 and lower IL-1β levels in PICF are related, (...truncated)