Diederik Hentenaar

42 Chapter 2 implants regarding levels of IL-6 (Melo et al. 2010 and Severino et al. 2016). Therefore, if IL-6 and TNF-α exert the same diagnostic potential as IL-1β remains inconclusive. In addition to the classical pro-inflammatory markers, the extracellular matrix degradation enzyme major matrix metalloproteinase 8 (i.e., MMP-8) is another frequently evaluated marker in PICF (Thierbach et al. 2016. Teixera et al. 2017). Comparable to what is found in patients with periodontal disease, there seems moderate evidence in the literature showing upregulated levels of MMP-8 in PICF of implants with peri- implant disease (Salvi et al. 2012 Ghassib et al. 2019, Alassy et al. 2019). However, a true comparison between peri-implant health and peri-implantitis for this marker was only sparsely studied (Arakawa et al. 2012, Wang et al. 2016, Janska et al. 2016). In line with the studies by Janska et al. (2016) and Arakawa et al. (2012), our study is one of the few studies who reported elevated levels for peri-implantitis implants compared to healthy implants. Therefore, the present study seems to enhance the moderate evidence of upregulated levels of MMP-8 in PICF of implants with peri-implantitis. It therefore might be hypothesized that MMP-8 may serve a promising role, in addition to IL-1β, to differentiate between peri-implant health and disease (Tierbach et al. 2016, Al-Majid et al. 2018, Alassy et al. 2019). Alongside with pro-inflammatory markers and MMP-8, MIP-1α/CCL3 is a protein with chemotactic (stimulation of cell migration) properties which plays an important role in inflammation and increased activation of bone resorption cells (osteoclasts). In a study by Petković et al. (2010) increased levels of MIP-1α/CCL3 in PICF of diseased implants were found when compared to healthy implants, whereas no difference between healthy and diseased sites was found for levels of MIP-1α/CCL3 in a more recent study by Bhavsar et al. (2019). In addition to this latter study, our findings also indicate that this marker does not seem to differentiate between peri-implant health and disease. To date, it therefore does not seem likely to expect a diagnostic potential role for MIP-1α/CCL3 in peri-implant disease, however more studies evaluating this marker are needed to confirm this finding. Another important chemotactic protein is MCP-1. This protein is considered the first discovered human chemokine and is a well-known chemoattractant for monocytes (Deshmane et al. 2009, Rollins 1996, Mulholland et. al. 2019). To the best of our knowledge, MCP-1 has not been previously evaluated in PICF of peri-implantitis patients. So far, we have only found two in-vitro studies on MCP-1 in the current literature reporting inconsistent outcomes (Bordin et al. 2009, Irshad et al. 2013). Our study seems the first to report on this marker in a clinical setting with no difference in the concentration levels of MCP-1 in the PICF between healthy and diseased implants. However there was a trend towards increased levels in diseased implants ( p = .136). To what extend this marker plays a role in peri-implant disease remains to be found.