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Meta-analyses, Orthopedics • Braz. oral. res. 36 • 2022 • https://doi.org/10.1590/1807-3107bor-2022.vol36.0055 linkcopy

Open-access Irisin effects on bone: systematic review with meta-analysis of preclinical studies and prospects for oral health

AuthorshipSCIMAGO INSTITUTIONS RANKINGS

Abstract:

Bone quality is an important issue in dentistry. Low bone density may be associated with more severe periodontitis, and may influence implant therapy success. Recent evidence suggests that physical activity can improve alveolar bone quality. Irisin is an exercise-mediated peptide that might be involved in this process. We assessed the effect of exercise and that of intra-peritoneal irisin administration on bone quality in healthy and osteoporosis-induced rodents. This study was registered at PROSPERO (CRD42020184140), and followed PRISMA guidelines. A search by two independent examiners was conducted in five databases and gray literature up to July 2021, without restrictions regarding language or date of publication. Initially, they analyzed retrieved titles and abstracts (n=3,844) based on eligibility criteria. Of this total, 19 studies remained for full-text reading, and 16 proceeded to the data extraction and quality assessment phases. Meta-analyses were conducted (n= 6 studies) to establish the effects of irisin administration on cancellous bone mineral density (BMD). Exercise or irisin administration enhanced bone quality, but the meta-analysis showed that BMD increased only slightly in osteoporotic rodents (BMD: mean difference 0.03 mg/cm3 - 95% CI 0.01-0.05). This indicates that they had no significant benefits on the bones of healthy animals. Implications of key findings evidence the potential of irisin as an agent able to mitigate bone loss caused by osteoporosis, an outcome that could favor dental rehabilitation. More studies investigating the effect of irisin on alveolar bone are needed to elucidate its therapeutic viability and implications.

Keywords:
Bone and Bones; Chronic Disease; Exercise; Dentistry; Physiology

Introduction

Bone quality is an important issue in dentistry. Systemic diseases such as obesity, diabetes mellitus and osteoporosis may lead to bone alterations, which are associated mainly with periodontitis and loss of alveolar bone.1,2 Low bone density could be a risk factor influencing implant success3 and impairment of tooth support structures4 during dental treatment. On the other hand, recent studies have shown that physical activity can improve the quality of alveolar bone.5,6 During exercise, muscle fibers under contraction release myokines, which exert local and systemic effects.7 These myokines play an important role as exercise-induced hormones that interact with bone.8

Irisin is an exercise-mediated peptide9 encoded by the fibronectin type III domain-containing protein 5 (FNDC5) gene,10 which regulates adipocyte and osteocyte metabolism11 through a specific αV-class of integrin receptors.12 The effects of irisin on bone seems to increase Atf4 and Runx2 expressions, resulting in an osteogenic effect.13 Irisin also reduces osteoclast differentiation and pro-inflammatory cytokines, and increases anabolic factors such as β-catenin, which induces osteoblast differentiation.14 Although some studies have indicated the positive relationship between exercise or recombinant-irisin injections (r-irisin) and bone anabolism,15-18 there is still no consensus substantiating this effect. Kim et al.12 reported that r-irisin injections increased sclerostin (Sost) expression in osteocytes, inducing bone resorption. On the other hand, Colaianni et al.19 found no effects of r-irisin on the bone of healthy rodents, whereas there was a preventive and curative effect on animals submitted to hindlimb osteoporosis. Furthermore, Colaianni and Grano20 found no effect on trabecular bone, but did observe an increase in cortical bone surface. As can be observed, the resulting consequences of exercise or r-irisin injections on bone are not yet conclusive.

Before irisin can be considered a potential agent for attenuating bone loss, it must be tested to determine whether there is enough evidence of its effects, based on pre-clinical studies. Animal protocols tend to evaluate homogenous samples with standardized conditions of feeding and environment. In addition, the irisin sequence is almost identical across most mammalian species.17 Irisin seems to have autocrine, paracrine and endocrine effects on oral and bone tissues21. Moreover, the evidence of bone stimulation makes it a promising agent for the dental treatment of patients with osteoporosis and other systemic conditions that induce alveolar bone loss. Thus, the aim of this systematic review and meta-analysis was to evaluate the effects of exercise and irisin injections on the bone quality of both healthy and osteoporotic rodents.

Methodology

Registration protocol and study design

This systematic review was registered at PROSPERO under protocol number 184140, and followed PRISMA- (Preferred Reporting Items for Systematic Review and Meta-Analysis) adapted guidelines.22 The methodology was adapted from Ferreira et al.23

Eligibility Criteria, Search Strategy and Data Extraction

Two independent reviewers searched animal studies published up to July 20, 2021, on five online databases (PubMed, Scopus, Web of Science, Embase and Science Direct). The PECO question focused on evaluating bone quality (Outcome) in rodents (Population) submitted to exercise or intra-peritoneal r-irisin administration (Exposure), in comparison with sedentary/placebo groups (Comparison). The search strategy involved the following keyword combinations: “irisin” OR “FNDC5” OR “fibronectin-type III domain-containing 5” AND “bone.” We used the filter “animal studies” when possible, with no restrictions on language. The searches were complemented using the OpenGrey database (“gray literature”), and similar terms.

The same two authors (L.J.P. and E.F.A.) conducted all the bibliographic searches, using the Mendeley® (www.mendeley.com) reference manager software to save studies retrieved from all the databases. Articles whose titles and abstracts did not meet the eligibility criteria were excluded, as well as opinion/technical reports, review articles, guidelines, and letters to the editors. Furthermore, articles not quantifying serum irisin levels, or investigating other therapeutic agents in association with irisin were also excluded. Two authors evaluated articles from the selected abstracts, and judged their suitability by reading their full texts independently of each other. Citations from the reference lists of selected articles were searched manually. The authors solved any disagreements in a consensus session.

Data extraction

The selected articles were submitted to data extraction including the following variables: authors, year of publication, study design, animal characteristics (source and sample size), average age, type of bone, type of physical activity, and irisin administration dose, as well as statistical analyses and main outcomes (Table 1). When the lack of information compromised data extraction, or caused risk of bias, an attempt was made to contact the authors by email in up to 4 consecutive weeks. Two independent authors determined the quality classification criteria and the risk of bias.

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Table 1
Data extraction of the selected animal studies.

Risk of Bias (RoB) assessment

We evaluated the risk of bias using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) RoB tool. This instrument contains 10 entries, related to 6 types of bias: selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases.24

Quality criteria assessment

A quality evaluation of the selected studies was made according to the Animal Research: Reporting In Vivo Experiments (ARRIVE) guidelines.25 This instrument contains a predefined score for 20 categories.25,26 Each criterion is graded, as previously reported.25-29 The sum of the scores ranged from zero to 36 points. The maximum score for each domain of the questionnaire was also calculated, as described by Javed et al.27 The Quality Score/Maximum Score ratio was also calculated, and generated three possible range coefficients, where 0.8–1 was “excellent,” 0.5–0.8 was “average,” and scores below 0.5 were considered “poor.”27

Statistical analysis

The multiple meta-analyses were performed by using the META package30 of R statistical software.31 We decided to include only studies that evaluated bone mineral density (BMD) using micro-computed tomography (µCT) in each forest plot, to avoid methodological heterogeneity in each meta-analysis. We evaluated healthy/sham and osteoporosis-induced animals separately, and included only studies evaluating intermittent irisin injection essays in the meta-analyses (excluding exercise studies). The inverse variance and the DerSimonian–Laird methods were used to estimate the between-study variance (τ2).

The mean difference (MD) was the effect measurement (i.e., the mean value in exposure groups – irisin administration – minus the mean value in the sedentary/placebo group – without irisin administration – for both healthy and osteoporotic animals. Random effect models were used for all the analyses. In this design, we used the mean value, the standard deviation and the sample size for each study, as reported (or estimated) for both the experimental and the control groups. The publication bias was not evaluated quantitatively by the Egger test or the funnel plot, despite the small number of studies grouped in the funnel plot.32

Results

Study selection and characteristics

A search of all the databases identified 3,844 references. After excluding duplicates, and reading the titles and abstracts, fourteen references were selected for full-text appraisal. Three articles were excluded after reading their full text.33-35 Kawao et al.33 and Chen et al.34 did not investigate irisin administration in vivo, and Xin et al.35 did not use intra-peritoneal injections (Table 2). Ultimately, sixteen articles were eligible for qualitative assessment. Six of these articles reported µCT-based assessment of cancellous BMD, and comprised the meta-analyses (Figure 1).

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Table 2
Articles excluded and reasons for exclusion (n = 3).
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Figure 1
Flow diagram of the screened articles adapted from the PRISMA statement.

Results for individual studies

Only four of the 16 selected studies investigated the effects of exercise on bone parameters. One submitted animals to low-intensity swimming, and another, to resistance ladder climbing (both for 8 weeks).14,15 The third article subjected one group of animals to voluntary exercise in a polycarbonate running wheel for 2 weeks, and evaluated i.p. 3.24 ng of r-irisin daily for two weeks in another group.16 The fourth evaluated the effects of an 8-week treadmill running protocol.36 The remaining 75% of the studies (12/16) evaluated irisin administration.12,13,17-19,37-39 Most doses of r-irisin were 100 μg/kg i.p. once a week for four weeks13,19,37,40 or eight weeks;39 or else twice a week for five weeks.41 However, Kim et al.12 administered 1 mg/kg/day of r-irisin i.p. for 6 consecutive days; while Narayanan et al.17 and Metzger et al.38 administered 18 ng/ml twice a week for 3 weeks; Metzger et al.,42 18 ng/ml injections of r-irisin i.p. three times a week for four weeks; and Xu et al.18, 1 mmol/l for an undetermined period.

Exercise increased serum irisin15, as well as FNDC5 and PGC1α mRNA levels in bone tissue.14,16,36 When investigating healthy rodents, no significant difference was found in bone mineral content or BMD.15,36 However, when osteoporosis was induced by a high-fat-diet (HFD), irisin administration resulted in BMD improvement.14

Administration of r-irisin caused no effects on the trabecular bone of healthy mice,13,19 but increased cortical tissue mineral density (C-TMD) and tibial cortical bone surface.13 When applying hindlimb suspension (HLS), r-irisin recovered both cortical and trabecular BMD,19 mitigated the apoptotic index with an increase in Bcl2/Bax, prevented an increase in empty lacunae and in Caspase-9 and Caspase-3 activations37, increased the bone formation rate, and lowered osteoclast surfaces, osteocyte TNF-α, IL-17, RANKL, and Sost in the unloaded hindlimb.42 When osteoporosis was induced by inflammatory bowel disease (IBD), r-irisin decreased the osteoclast surface, and increased the osteoid surface and the bone formation rate17, in addition to mitigating the increase in TNF-α, IL-6, RANKL, OPG, Sost and annexin V.38 After Orchidectomy/Ovariectomy (ORX/OVX), r-irisin treatment significantly prevented trabecular BMD, and bone volume/total volume (BV/TV) reduction39,41, increased Tb.Th, Tb.N, and reduced Tb.Sp.18 He et al.43 reported that irisin treatment caused an increase in bone volume fraction, in trabecular number and connection density, and an improvement in the structure model index, besides reducing serum levels of osteocalcin, bone alkaline phosphatase, TRAP, calcium and phosphorus.40

Conversely, the results found by Kim et al.12 were the opposite of all the other studies, namely r-irisin injections (daily for 6 days) increased the Sost mRNA level in 8-week-old wild-type C57BL/6J mice. Moreover, FNDC5 null mice presented significantly lower levels of RANKL mRNA in bones, whereas the OPG was not altered (Table 1).

Bias risk assessment and quality criteria assessment

Data extraction (Table 1) and bias risk assessment (Table 3) indicated low risk of bias for most studies in “selective outcome reporting” (100%) and “baseline characteristics” (93.8%). The “sequence generation” was considered adequate for 43.8% of the studies. On the other hand, there was a high risk of bias for almost all the studies in both the “allocation concealment” and “blinding of participants and personnel” domains. Most studies did not provide sufficient information (or left it unclear) regarding the “random outcome assessment,” or presented “incomplete outcome data” (Table 3).

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Table 3
Assessment of risk of bias in included studies.

The total score obtained using the ARRIVE guidelines ranged from 19 to 34 points (mean score 27.87 ± 4.51), from a maximum of 36. Nine categories scored “excellent” (between 0.8-1.0), and nine categories were classified as “average” (between 0.5-0.8). Only two categories were classified as “poor” (below 0.5), namely allocation and results baseline data. (Table 4).

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Table 4
Scores of quality assessment according to ARRIVE guidelines of the studies including animal models.

Quantitative analysis of the studies (meta-analyses)

Six of the 16 articles included in the systematic review presented BMD data and were included in the meta-analyses and forest plots (Figure 2). There was moderate to high heterogeneity among the studies (I2 = 31% for non-osteoporotic, and 88% for osteoporotic animals). Random effect models were preferred.

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Figure 2
Forest plot and meta-analysis of bone mineral density (BMD) in healthy/sham and osteoporosis-induced animals receiving intermittent irisin injections.

The BMD for healthy/sham animals receiving irisin, in comparison with animals receiving placebo, indicated a random effect (MD) of zero (95% CI −0.01; 0.01), whereas the random effect (MD) for BMD in osteoporosis-induced animals receiving irisin was 0.03 mg/cm3 (95% CI 0.01-0.05), in comparison with animals receiving placebo (with a right dislocated diamond without crossing the midline) (Figure 2).

Discussion

The findings of the present study indicated that exercise and r-irisin administration brought about significant positive effects on bone tissues. The meta-analysis showed increased BMD in osteoporosis-induced rodents (but not normal animals) after intermittent irisin injection. These results are important to dentistry, since oral signs and symptoms associated with osteoporosis can cause physical and psychological stress.44

The models used to induce bone loss varied among the studies. In these models, bone loss could be linked to systemic and/or local inflammation. An HFD14 elevates fat accumulation and pro-inflammatory cytokines (TNF-α, IL-1, and IL-6), and, in turn, induces osteoclast differentiation and activity by regulating the receptor activator of NF-κB (RANK) and RANK ligand (RANKL) pathways.45,46 Ovariectomy18,39 induces estrogen deficiency, which enhances the production of interleukin IL-1, IL-6, IL-7, TNF-α and the granulocyte macrophage colony-stimulating factor (GMCSF) by immune cells, leading to osteoclastogenesis and bone resorption.47 Mechanical unloading19,37 induces osteocyte apoptosis and the release of intracellular molecules.48 These molecules (such as high mobility group box 1 - HMGB1, purine metabolites, heat-shock proteins, and uric acid)47,49 induce the recruitment and activation of macrophages, with consequent secretion of TNF-α, IL-6 and IL-1, initiating inflammatory bone loss.47,48,50 This mechanism involves upregulation of the RANKL/OPG ratio, hence interfering with Wnt/β-catenin signaling, and increasing Sost production.37 Inflammatory bowel disease (IBD)17,38 initiated in the gut results in increased osteocytes positive for TNF-α, IL-6, RANKL and Sost.51

The anti-osteoporotic mechanism of irisin seems to involve not only an increase in the number and activity of osteoblasts,16 but also the suppression of Sost.13 Sost is upregulated by the inflammatory cytokine TNF-α, which is associated with an increase in RANKL, leading to increased osteoclastic activity.17,52 The more pronounced effects of irisin on osteoporosis-induced animals might be related to the anti-inflammatory activity of irisin, since muscle-specific PGC-1α knockout animals present upregulation of local muscle inflammatory genes. Moreover, inflammatory diseases have low levels of serum irisin.53

Although the great majority of retrieved studies indicated no or only mild positive effects of irisin on bone, Kim et al.12 found contrasting results, in which irisin increased Sost expression in osteocytes. The explanation for these discrepancies was attributed to differences in the therapeutic scheme of irisin injections. Supposedly, the positive effects of irisin on bone depend on intermittent treatment (reported in all the studies included in the meta-analyses), whereas continuous treatment induces bone resorption12. Only the study by Kim et al.12 evaluated the effect of continuous irisin administration on bone using μCT, hence precluding any comparison. Indeed, a more recent study by Storlino et al.37 found that Sost mRNA was severely downregulated only upon intermittently administrated irisin, even though other key genes expressed by MLO-Y4 cells were modulated by irisin treatment, administered either continuously or by intermittent short pulses.

Most studies researched intermittent r-irisin administration, while only four investigated exercise models. Kim et al.15 showed that progressive resistance training did not alter bone quality, including bone mineral content (BMC) and BMD. On the other hand, Zhang et al.16 found that voluntary exercise increased irisin production and osteogenesis in mice. In the latter study, mice ran an average of five thousand meters a day, whereas the most frequent exercise protocols for rodents call for a one-hour session, 3 to 5 days a week. Increased levels of irisin from physical exercise may vary depending on training intensity and duration. Myokine delivery depends on the intensity and duration of the exercises.54 Investigations into the effects of different types of exercises and other variables, such as intensity and frequency, are important to gain a better understanding of how irisin works in bone remodeling. The comparison among studies was hindered by their heterogeneity of bone parameters, irisin quantification and exercise protocols.

It is important to consider that we selected only studies using μCT. Moreover, we also conducted subgroup meta-analyses with and without osteoporosis in studies evaluating intermittent irisin injections, but excluded exercise and continuous irisin administration studies in the meta-analyses. Even after controlling all these aspects, we observed that osteoporosis-induced BMD meta-analyses showed high heterogeneity. Heterogeneity over 60% is very common in a meta-analysis that uses animal studies. Rather than abort the meta-analysis design, we felt that the random effect model would be more suitable, because it fits the variation in animal studies better.55,56

In evaluating the quality criteria accessed using the ARRIVE guidelines,25 we observed that the categories of “experimental procedure,” “sample size,” and “results baseline data” received the lowest ratings. Previous research evaluating the quality of interventional animal studies in rheumatology using the ARRIVE guidelines reported that none of the 41 studies that were investigated reported sample size calculation, or details regarding the animal allocation method, randomization or assessor blinding.60 In the present study, only one article clearly reported the sample size calculation.17 This is a very significant shortcoming, since studies with an inadequate sample size could provide false-negative results, thus leaving potential findings undetected. We believe that the lack of some information may have resulted from restrictions placed on the word count (e.g., abstracts). However, several important journals are adopting the ARRIVE guidelines to improve the reporting quality of publications.60

In the present study, we used the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) RoB tool24 to evaluate the quality of the retrieved animal studies. Our results were similar to those found by previous systematic reviews of pre-clinical studies regarding the risk of bias.57 Bias due to inadequate information about randomization and blinding is frequent in animal experiments.58 Attention to these items is crucial to avoid subjective outcome measurements, and to reduce implementation or measurement bias.59

Limitations of the present research protocol relate to the lack of information contained in several studies, regarding such factors as randomization, sample size calculation and blinding. However, the overall scores of the ARRIVE guidelines indicated almost 88% adherence (considered as average or excellent - Table 3). Nevertheless, investigations probing the effects of different types of exercises (swimming, ladder climbing or running wheel; voluntary or forced activity), divergent dosages of r-irisin (and frequency), and different sources of osteoporosis induction hindered making adequate comparisons. Worthy of note, the irisin effect maintained the same overall direction in the majority of studies, as indicated in the meta-analyses.

Previous research conducted by our group has shown the positive effects of exercise on alveolar bone quality. Physical practice attenuated the bone loss and epithelial attachment loss levels of rats with ligature-induced periodontal disease. Animals with periodontal disease (PD), submitted to training, presented lower TNF-α expression in periodontal tissues, whereas IL-10 was higher. The TNF-α/IL-10 ratio was also lower in PD-affected animals that exercised, compared with sedentary ones.5 Moreover, a systematic review using human observational studies indicated that physical activity was directly associated with a lower occurrence of periodontitis.23 Likewise, aerobic and resistance training reduced orthodontic tooth movement, enhanced the quality of maxillary bone, and increased BMD, trabecular BV, and the BV/TV ratio.6 In the last cited study, the FNDC5 gene expression of the maxillary bone subject to orthodontic tooth movement was negatively affected. This suggests that the local synthesis and release of pro-inflammatory metabolites during tooth movement61,62 might downregulate irisin activity.63 Irisin was recently discovered in 2012. Since then, its physiological role has been under ongoing investigation. Understanding how irisin functions may be key to comprehending many diseases and their development.64

Conclusions

Based on the present findings, exercise and/or irisin injections have induced significant bone quality improvements in osteoporotic rodents, in contrast to their non-significant effects on healthy ones. Implications of key findings evidence the potential of irisin as an agent able to mitigate bone loss caused by osteoporosis, an outcome that could favor dental rehabilitation. More studies investigating the effects of irisin on alveolar bone are needed to elucidate its therapeutic viability and implications.

Acknowledgments

The authors would like to thank the National Council for Scientific and Technological Development (CNPq), the Higher Education Personnel Improvement Coordination (Capes), and the Minas Gerais State Research Support Foundation (Fapemig).

References

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Publication Dates

  • Publication in this collection
    15 Apr 2022
  • Date of issue
    2022

History

  • Received
    04 Dec 2020
  • Reviewed
    12 Dec 2021
  • Accepted
    26 Jan 2022
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