Resumen de Estimation of Bone Loss Biomarkers as a Diagnostic Tool for Peri-Implantitis
Mia Rakic, Xavier Struillou, Aleksandra Petkovic-Curcin, Smiljana Matic, Luigi Canullo, Mariano Sanz Alonso, Danilo Vojvodic
Background: The aims of this study are to estimate the profile of bone loss biomarkers in peri-implant tissues and to identify potential prognostic biomarkers of peri-implantitis.
Methods: Peri-implant crevicular fluid samples collected from 164 participants (52 patients with peri-implantitis, 54 with mucositis, and 58 with healthy peri-implant tissues) were analyzed using enzyme-linked immunosorbent assays to evaluate concentrations of the receptor activator of nuclear factor-κB (RANK), soluble RANK ligand (sRANKL), osteoprotegerin (OPG), cathepsin-K, and sclerostin.
Results: Concentrations of RANK, sRANKL, OPG, and sclerostin were significantly increased in patients with peri-implantitis compared with patients with healthy peri-implant tissues. Comparisons between peri-implantitis and mucositis demonstrated significantly higher values of sclerostin in peri-implantitis samples. Comparisons between mucositis and healthy peri-implant tissues showed significantly increased levels of RANK and cathepsin-K in mucositis.
Conclusion: These results are suggestive of a role of sRANKL, OPG, and sclerostin as prognostic biomarkers in peri-implantitis.
Currently, implant placement is a key therapeutic solution1 in restorative dentistry because of its biomimetic concept and high predictability in the attainment of long-term functional and esthetic outcomes.2 However, different from the natural dentition, the absence of periodontal ligament attachment puts the peri-implant tissues at a higher of risk of infection and trauma.3 These tissues were shown to be less resistant to increased levels of bacterial plaque accumulation, and the progression of the chronic inflammation as a response to this bacterial challenge seems to be more rapid and intense, directly affecting the bone tissue and, hence, causing breakdown of the bone-to-implant interface. Moreover, the scarcity of pain receptors in this bone-to-implant interface makes the symptomatology of peri-implantitis usually minor and scattered,4 which highlights the importance of a timely diagnosis to prevent these diseases or at least to treat them at an early stage.5 Numerous studies were conducted to evaluate the accuracy of routine clinical and radiologic diagnostic procedures for peri-implant diseases.6-9 In brief, the clinical parameters used in the diagnosis of periodontal diseases, including bleeding on probing (BOP), probing depth (PD), and relative clinical attachment level (rCAL), were considered not sensitive enough to provide accurate diagnostic information on risk rate, disease onset and activity, prognosis, and treatment outcomes when applied to the diagnosis of peri-implant diseases. This is probably a result of the different biology of the peri-implant tissues compared with periodontal tissues6,8,10 and other factors related to the implant and its design, as well as to the prosthetic superstructure that may clearly affect the accuracy of probing, thereby decreasing its value.7 A biomarker is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.11 Therefore, biomarkers may be considered a potential diagnostic solution with the ability to compensate for some of the referred limitations of the routine clinical tools when applied to implant diagnostics. Many studies were conducted to study biomarkers in peri-implant tissues, but the results were not consistent.12-17 Regarding biochemical biomarkers, this lack of consistency is probably attributable to the nature of the peri-implant crevicular fluid (PICF) as a diagnostic medium.8 PICF is the oral fluid with the lowest protein content, which represents a challenge when using commercial diagnostic assays, generally designed for diagnostic media with significantly greater protein content, such as serum. Additionally, the flow of PICF is relatively scarce when compared with the other media, such as serum,18 which adds greater difficulty in standardizing the detection levels, with some studies reporting the data in percentages of detection, others in biomarker levels, and others in concentrations. This lack of consistency in the results reported in the literature complicates the interpretation of the diagnostic value of these biomarkers. Recent studies evaluating bone loss (BL) biomarkers comparing patients with peri-implantitis and chronic periodontitis demonstrated a good level of recovery and significant correlations between measured markers and corresponding clinical parameters.19,20 In these studies, an optimized working protocol was reported that demonstrated 100% detectability rate, and significant correlations with clinical parameters were reached for almost all parameters. After optimization of the working protocol, the next step in promoting biomolecule as biomarker is usually a cross-sectional study to profile the marker concentration under different tissue conditions. This is particularly important in the case of bone markers because they exhibit substantial short-term and long-term fluctuations under a variety of factors.21 Inflammatory osteoclastogenesis represents the central pathologic pattern of peri-implantitis. This process is mediated by proinflammatory mediators,22 but it is ultimately performed by the regulators of osteoclastogenesis. Its main regulators are the receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG), which inhibit this ligand–receptor interaction.23 Therefore, the RANK–RANKL interaction leads to a differentiation of osteoclast progenitors and enhances the activity of mature osteoclasts,24 whereas OPG antagonizes this differentiation.25 RANK is localized on the surface of preosteoclasts and osteoclasts and becomes activated by both autoligation and RANKL ligation.26 Both mechanisms are stimulated by a critical concentration of proinflammatory mediators and lipopolysaccharide (LPS).27 When activated, RANK leads to the intracytoplasmic release of several transcription factors coding for proinflammatory cytokines, which further enhance the osteoclast activity.22,28 Furthermore, activated osteoclasts express cathepsin-K,29 the unique lysosomal cysteine protease with the ability to degrade bone matrix, including collagen type 1, osteopontin, and osteonectin under acid pH.30 Therefore, the presence of this enzyme is considered a highly specific marker of active bone resorption and osteoclast activity.29 Sclerostin protein is expressed by cells involved in bone metabolism, such as osteocytes, hypertrophic mineralized chondrocytes, and cementocytes,31,32 and negatively regulates bone formation by reducing the mineral content of the bone including the amount of trabecular bone as well as cortex thickness. Hence, sclerostin is considered a biomarker that negatively regulates bone formation in a way of antagonizing bone morphogenic proteins.33 Sclerostin is reported to be upregulated by proinflammatory cytokines34 and excessive load.35 Based on these facts, this bioprotein may also serve as an indicator of peri-implantitis, not only by the presence of chronic inflammation but also the presence of inappropriate biomechanical forces.
This cross-sectional study aims to prove the hypothesis that the increased PICF levels of RANK, RANKL, OPG, cathepsin-K, and sclerostin are associated with peri-implantitis and hence could be considered potential candidates as prognostic biomarkers of peri-implantitis.
