Moderate evidence exists for four microRNAs as potential biomarkers for tendinopathies and degenerative tendon ruptures at the upper extremity in elderly patients: conclusion of a systematic review with best-evidence synthesis
Journal of Experimental Orthopaedics volume 10, Article number: 81 (2023)
The aim of this systematic review was to investigate tendon-specific microRNAs (miRNAs) as biomarkers for the detection of tendinopathies or degenerative tendon ruptures. Also, their regulatory mechanisms within the tendon pathophysiology were summarized.
A systematic literature research was performed using the PRISMA guidelines. The search was conducted in the Pubmed database. The SIGN checklist was used to assess the study quality of the included original studies. To determine the evidence and direction of the miRNA expression rates, a best-evidence synthesis was carried out, whereby only studies with at least a borderline methodological quality were considered for validity purposes.
Three thousand three hundred seventy studies were reviewed from which 22 fulfilled the inclusion criteria. Moderate evidence was found for miR-140-3p and miR-425-5p as potential biomarkers for tendinopathies as well as for miR-25-3p, miR-29a-3p, miR-140-3p, and miR-425-5p for the detection of degenerative tendon ruptures. This evidence applies to tendons at the upper extremity in elderly patients. All miRNAs were associated with inflammatory cytokines as interleukin-6 or interleukin-1ß and tumor necrosis factor alpha.
Moderate evidence exists for four miRNAs as potential biomarkers for tendinopathies and degenerative tendon ruptures at the upper extremity in elderly patients. The identified miRNAs are associated with inflammatory processes.
Tendons are a key element in the musculoskeletal system for the generation of movements due to their ability to transmit and withstand forces . However, pathological tendon conditions such as tendinopathies are prevalent in the entire population with incidences of up to 10.52 per 1,000 persons per year . Tendinopathies are characterized by persistent tendon pain and loss of function associated with mechanical loading  and could cause a reduced life quality , impairments of work and sportive performances , and underestimated high socio-economic costs . The pathogenesis is understood as a continuum model with the end stage of degenerative tendinopathy , where symptoms may persist for decades . Since associated degenerative changes are present in 97% of all ruptured tendons , it is assumed that tendinopathies can cause such acute severe tendon injuries . However, high-quality evidence for effective preventive measures for tendinopathies is lacking [11, 12] and early clinical management is challenging due to asymptomatic early stages  as well as often ignored minor symptoms . In this context, established clinical routine diagnostics such as anamnesis, clinical examination, and tendon imaging  are suitable for the diagnosis of manifested tendinopathies, but inappropriate for asymptomatic early stages. Thus, more research is needed to evaluate diagnostic tools for the early diagnosis of tendinopathies and associated degenerative tendon ruptures, including the identification of potential biomarkers.
MicroRNAs (MiRNAs) are short noncoding RNA molecules that bind to complementary messenger-RNAs to regulate their activity . In humans, miRNAs are expressed in a cell- and tissue-specific manner [17, 18]. They can be detected in a variety of different body fluids including blood, tears, or saliva . MiRNAs are suitable diagnostic biomarkers , because they are protected from endogenous RNAse activity  and can endure freeze–thaw cycles . In this context, miRNAs have been evaluated as non- or minimal-invasive biomarkers for numerous diseases including Alzheimer , multiple sclerosis , heart failure , or various cancer types [26,27,28], but little is known with respect to degenerative tendon conditions yet.
MiRNAs have been associated with the tendon tissue pathophysiology. It has been demonstrated that miRNAs could reduce adhesion, enhance remodeling, and promote angiogenesis in the context of tendon healing . Also, miRNAs are known to regulate a variety of different genes related to tendon healing and tenogenesis . To date, there are two systematic reviews investigating the relationship between the expression rates of miRNAs and tendon tissue functions. Dubin et al.  investigated the effect of miRNAs on tenocytes and tendon-related gene expression. They show that miRNAs have both positive and negative effects on the tendon tissue homeostasis. Giordano et al.  examined the therapeutic potential of miRNAs in the context of tendon healing. The authors conclude that miRNAs could serve as useful therapeutic targets due to their influence on the expression of cytokines and differentiation and proliferation of stromal cell lines involved in the composition of the extracellular matrix. However, there is no systematic review questioning, if miRNAs can be used as biomarkers for pathological tendon conditions. Therefore, the aim of this systematic review was to investigate tendon-specific miRNAs as biomarkers for the detection of tendinopathies or degenerative tendon ruptures. Also, the regulatory mechanisms of miRNAs within the tendon pathophysiology were summarized.
The systematic review was conducted using the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA) . The inclusion and exclusion criteria were determined using a PICO(S) scheme: i.e., population (P), intervention (I), comparison (C) outcome (O), and study design (S) . Additionally, the item "other" was included to account for further criteria (Table 1). The inclusion criteria were: (i) human studies including patients with tendinopathies or degenerative tendon ruptures; (ii) tendon-specific miRNAs quantified in the tissue and/or circulation; (iii) primary data published in original investigations; (iv) publication language in English or German; and (v) full text availability. Studies were excluded, when the miRNAs were not specified. All methodological steps were conducted by one author and a second validated them. In terms of uncertainties, it was discussed until a consensus was reached. Due to the non-invasive character, no ethical approval was considered.
Literature search strategy and study selection
The search was performed in the meta-database Pubmed on 04/25/2022 and was not restricted to a specific time period. To find relevant studies, a search line was elaborated using the inclusion and exclusion criteria. The search line included the following terms: (micro RNA OR miR OR miRNA OR microRNA OR circRNA OR circulating RNA OR ciRNA) AND (tendon OR tendinopathy OR tendinosis OR tendinitis OR tendosynovitis OR tenocytes OR ruptures OR connective tissue) AND (physiology OR pathology OR pathophysiology OR maladaptation OR load OR intervention OR adaptation OR baseline OR timepoint OR pre-post OR comparison). Additionally, the reference list of two previous systematic [31, 32] and five previous narrative reviews [29, 30, 35,36,37] within the particular research field were screened for further suitable studies. After duplicates were removed, the abstracts and full texts of the remaining studies were checked for their fit by taking the eligibility criteria into account.
Risk of bias assessment
The study quality and associated risk of bias was determined using the Scottish Intercollegiate Guidelines Network (SIGN) checklist . Therefore, the particular checklist for randomized controlled trials, cohort studies, case–control studies, and diagnostic and economic studies was used. The checklists consisted of 10–15 items to test the internal validity of the studies. The items were rated as "Yes" (Y), "No" (N), "Can't say" (CS), or "not applicable" (NA). The overall rating of the studies involved the following outcomes: "high quality", "acceptable quality", "borderline quality", or "unacceptable quality", as described in detail elsewhere .
The data extraction of the studies was conducted according to the PICO(S) scheme. For validity, studies with an unacceptable quality were not considered, as conducted previously . Due to the found heterogeneity in terms of the methodologies and results of the studies, no meta-analysis was performed. Instead, a best-evidence synthesis was conducted to clarify the evidence and direction of the miRNA expression rates . The expression rates and their associations with tendinopathies or degenerative ruptures were classified as: upregulated (↑), downregulated (↓), or neutral ( →), which means that no clear pattern was given. To increase the validity, only miRNAs that were found, at least in part, twice in different studies were considered in the best-evidence synthesis. An exception was made for the study by Thankam et al. , where only the 10 most up- and down-regulated miRNAs were included to reduce the amount of data from this comprehensive microarray study including more than 235 miRNAs. Nevertheless, miRNAs that occurred more than two times were matched to the study by Thankam et al. , if they were not already included in the 10 most up- or down-regulated in this study. Table 2 summarizes the applied criteria for the best-evidence synthesis according to Asker et al. , whereby the final ratings were as follows: “strong evidence”, “moderate evidence”, “limited evidence”, and “no evidence”.
Literature search strategy, study selection, and risk of bias
Figure 1 shows the results of the literature search strategy and study selection. 3,345 and 25 articles were found using the search line and reference lists, respectively. After duplicates were removed, 3,346 articles remained. Thereof, 3,324 articles were excluded due to different reasons (Fig. 1). Thus, a total of 22 studies were finally included and considered for the risk of bias assessment.
Table 3 shows the results of the risk of bias assessment by the SIGN-checklist. Of the 22 considered studies, one study was classified as high quality , three studies as acceptable [42,43,44], 14 as borderline [40, 45,46,47,48,49,50,51,52,53,54,55,56,57], and four as unacceptable [58,59,60,61].
Table 4 summarizes the study characteristics of the 22 studies according to the PICO(S) scheme. Concerning the study design, there were 13 case–control [40,41,42,43,44,45,46, 48, 49, 52, 54, 55, 58] and 9 controlled studies [47, 50, 51, 53, 56, 57, 59,60,61]. In total, miRNAs were quantified for 15 times in the tissue [40, 42,43,44, 48, 49, 51,52,53,54,55, 57, 59,60,61] and two times in the circulation [46, 47]. Two studies considered both [41, 50] and in three studies the sample was unclear [45, 56, 58]. With respect to the tissue, the biopsy was taken four times from the supraspinatus tendon [42, 44, 48, 53], three times from the bicep tendon [40, 54, 55], three times from the Achilles tendon [49, 52, 59], twice from both the supraspinatus and subscapularis tendons [43, 51], twice from patellar tendon [57, 60], and once from the hamstring tendon . In regard to the circulation, miRNAs were detected in one study each from whole blood  and saliva . In the study in which the samples were taken from both the tissue and circulation, measurements were taken from venous blood as well as from the supraspinatus and subscapularis tendons . In another study, mesenchymal stem cells were harvested from bone marrow and tendon stem cells from hamstring tendon and the effect of miR-29b-3p on the expression of transforming growth factor ß1 (TGF-ß1) and type I collagen was tested . To quantify miRNA expression rates, 17 studies used PCR methodology [41, 42, 44,45,46,47,48,49,50,51,52,53, 56, 57, 59,60,61], four studies performed microarray analysis [40, 54, 55, 58], and one study used RNA PICO quantitation method . Concerning the microarray approaches, three studies used biceps tendon samples [40, 54, 55], whereas the sample was unclear in one study . Table 5 summarizes the regulatory mechanisms of the miRNAs of the included 22 studies.
Synthesis of results of miRNAs
Since only studies with, at least in part, a borderline level of evidence were considered for validity purposes, a total of 18 studies were included in the best-evidence synthesis [40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57]. Table 6 shows the corresponding results of miRNAs and their expression patterns associated with tendinopathies and degenerative tendon ruptures. A total of 18 different miRNAs were found that could be detected for more than two times. An evidence level for 12 different miRNAs could be related. Particularly, moderate evidence was found for four miRNAs (miR-25-3p, miR-29a-3p, miR-140-3p, miR-425-5p) and limited evidence for eight miRNAs (miR-99a-5p, miR-145-5p, miR-151a-3p, miR-191-5p, miR-199a-5p, miR-297, miR-532-5p, let-7b-5p). For four miRNAs that appeared multiple times, no evidence (miR-29a, miR-29b-3p miR-608, miR-1273 g-3p) could be identified, because the regulatory pattern was unclear. For two miRNAs (miR-100-5p and miR-222-3p), the results were conflicting.
The main finding was that moderate evidence was found for miR-140-3p and miR-425-5p as potential biomarkers for tendinopathies as well as for miR-25-3p, miR-29-a-3p, miR-140-3p, and miR-425-5p for the detection of degenerative tendon ruptures. This evidence applies to tendons at the upper extremity in elderly patients. All miRNAs were associated with inflammatory cytokines as interleukin-6(ß) and tumor necrosis factor alpha.
Moderate evidence exists for miR-25-3p, miR-29a-3p, miR-140-3p, and miR-425–5 as potential biomarkers for pathological tendon conditions (Table 6). Our findings are in line with those of previous systematic reviews [31, 32], showing that the miR-29 family have a special importance in such tendon diseases. Our review adds that moderate evidence was found for miR-25-3p, miR-29a-3p, miR-140-3p, and miR-425-5p as biomarkers for pathological tendon conditions (Table 6); exclusively, at the upper extremity associated either with biceps [40, 54], supraspinatus/subscapularis [41, 43], or supraspinatus  tendons in elderly patients. Furthermore, significant differences in the circulation were found for both miR-140-3p and miR-425-5p for tendinopathic tendons compared with healthy tendons  and for miR-25-3p, miR-29a-3p, miR-140-3p, and miR-425-5p in degenerative tendon ruptures compared with healthy tendons . However, the sampling was exclusively taken in elderly [41, 43, 44] or patients with unknown age [40, 54]. Thus, there is not only a need for more high-quality studies, but also for more potential miRNAs in tendon diseases at the lower extremity and in patients at younger ages.
MiR-140-3p and miR-425-5p could serve as potential biomarkers for tendinopathies (Table 6). For both miRNAs, significantly decreased expression levels were observed in tendinopathic tendons in the circulation, when compared to healthy tendons . In addition, the study by Thankam et al.  found that both miRNAs were significantly decreased in tendon injuries with glenohumeral arthritis compared to healthy control tendons. However, it is important to emphasize that these were not tendinopathic, but tendons with massive tears. Moreover, miR-140-3p was significantly decreased in tendinopathic tendons with glenohumeral arthritis compared to tendinopathic tendons without glenohumeral arthritis . Thus, miR-140-3p and miR-425-5p may be potential diagnostic biomarkers for tendinopathies, but the results should be taken with caution due to the association found with further diseases.
MiR-25-3p, miR-29-a-3p, miR-140-3p, and miR-425-5p could serve as potential biomarkers for the detection of degenerative tendon ruptures (Table 6) due to the significant downregulation in the circulation in degenerative ruptured tendons compared with healthy tendons . Here, miR-29a-3p and miR140-3p were shown to be significantly downregulated in both tissue and circulation in degenerative ruptured tendons . Additionally, the study by Thankam et al.  demonstrated that miR-25-3p, miR-29a-3p, miR-140-3p, and miR-425-5p were also significantly downregulated in tendon ruptures of the bicep tendon compared with healthy control tendons. In the study by Thankam et al. , it was shown that miR-25-3p, miR-29a-3p, and miR-140-3p were also significantly downregulated in tendinopathic tendons with glenohumeral arthritis compared with tendinopathic biceps tendons. Furthermore, miR-29a-3p was downregulated in tissue in tendinopathic supraspinatus tendons compared with healthy subscapularis tendons . In a study by Leal et al. , miR-29a-3p was inversely correlated with various matrix metalloproteinases (MMPs), but there were no significant differences in the expression rates of miR-29a-3p between healthy and ruptured supraspinatus tendons. Thus, there seems to be a relationship between miR-25-3p, miR-29a-3p, miR-140-3p, and miR-425-5p with degenerative tendon ruptures. MiR-140-3p and miR-425-5p were significantly downregulated in both tendinopathic tendons and degenerative tendons in the circulation compared with healthy control tendons. A progressive decrease in expression levels was also observed for the two miRNAs in relation to the severity of tendon degeneration . This suggests that miR-140-3p and miR-425-5p may contribute to the pathogenesis and/or progression of degenerative rotator cuff diseases in elderly patients, requiring further validation.
Different regulatory mechanisms of miRNAs in tendon tissue are discussed in the literature. Briefly, miR-25-3p can be considered as a potential tumor biomarker in breast cancer  or osteosarcoma . In both cases, cytokines such as interleukin-6 (Il-6) influence tumor genesis [64, 65] and Il-6 also plays a role in tendon ruptures . For miR-29a-3p, it has been shown to be an eligible biomarker in colorectal cancer  and tuberculosis , among others. In both tuberculosis and carciogenesis, Il-6 play an important role again [68, 69]. Regarding the miR-140-3p, it is evident that this miRNA is also significantly down-regulated in human chondrocytes in glenohumeral arthritis , among others. MiR-140-3p was shown to reduce the concentration of interleukin-1ß (IL-1ß) induced inflammatory factors . IL1-ß plays a crucial role mainly in the inflammatory phase of tendon healing , but it has also been shown that it has a significant role in arthritis . Gu et al.  demonstrated that miR-425-5p is associated with both tumor necrosis factor alpha (TNF-alpha) and IL-1ß, which also plays a role in tendinopathies . Overall, all miRNAs for which moderate evidence was found are associated with specific inflammatory cytokines. Therefore, it is unclear, if these miRNAs can serve as potential biomarkers for tendon diseases or significantly alter their expression patterns tissue-independently due to inflammatory processes. More experimental high-quality research is needed to validate miR-25-3p, miR-29a-3p, miR-140-3p, and miR-425-5p as tendon-specific biomarkers.
Although this systematic review increased the knowledge on miRNAs as potential biomarkers for tendon diseases, there are few limitations. While Pubmed can be regarded as the most comprehensive database, it has to be noted that it was the only platform used for the literature search. Additionally, all methodological steps of our review were conducted only by one author. However, a second author carefully validated the entire proceed and all outcomes independently, which is not fully compliant with the PRISMA guidelines. More experimental high-quality studies are needed to investigate miRNAs in both the tissue and circulation to validate them as biomarkers for tendinopathies or degenerative tendon ruptures; especially, at the lower extremity and in younger individuals. Also, more basic research is required to better understand the regulatory mechanisms of miRNAs within the tendon pathophysiology.
Our systematic review based on a best-evidence synthesis suggests that moderate evidence exists for four miRNAs as potential biomarkers for tendinopathies and degenerative tendon ruptures at the upper extremity in elderly patients. The identified miRNAs are associated with inflammatory processes. More experimental high-quality research to validate the four miRNAs is required.
Availability of data and materials
The datasets used and analysed during the current study are available from the corresponding author on reasonable request.
Preferred Reporting Items for Systematic Reviews and Meta-analyses
Range of motion
Scottish Intercollegiate Guidelines Network
Transforming growth factor ß1
Tumor necrosis factor alpha
Gaut L, Duprez D (2016) Tendon development and diseases. Wiley Interdiscip Rev Dev Biol 5:5–23. https://doi.org/10.1002/wdev.201
Albers IS, Zwerver J, Diercks RL, Dekker JH, van den Akker-Scheek I (2016) Incidence and prevalence of lower extremity tendinopathy in a Dutch general practice population: a cross sectional study. BMC Musculoskelet Disord 17:16. https://doi.org/10.1186/s12891-016-0885-2
Scott A, Squier K, Alfredson H, Bahr R, Cook JL, Coombes B, de Vos R-J, Fu SN, Grimaldi A, Lewis JS, Maffulli N, Magnusson SP, Malliaras P, Mc Auliffe S, Oei EHG, Purdam CR, Rees JD, Rio EK, Gravare Silbernagel K, Speed C, Weir A, Wolf JM, van den Akker-Scheek I, Vicenzino BT, Zwerver J (2020) ICON 2019: International Scientific Tendinopathy Symposium Consensus: Clinical Terminology. Br J Sports Med 54:260–262. https://doi.org/10.1136/bjsports-2019-100885
Lewis TL, Yip GCK, Robertson K, Groom WD, Francis R, Singh S, Walker R, Abbasian A, Latif A (2022) Health-related quality of life in patients with Achilles tendinopathy: Comparison to the general population of the United Kingdom. Foot Ankle Surg 28:1064–1068. https://doi.org/10.1016/j.fas.2022.02.018
de Vries AJ, Koolhaas W, Zwerver J, Diercks RL, Nieuwenhuis K, van der Worp H, Brouwer S, van den Akker-Scheek I (2017) The impact of patellar tendinopathy on sports and work performance in active athletes. Res Sports Med 25:253–265. https://doi.org/10.1080/15438627.2017.1314292
Hopkins C, Fu S-C, Chua E, Hu X, Rolf C, Mattila VM, Qin L, Yung PS-H, Chan K-M (2016) Critical review on the socio-economic impact of tendinopathy. Asia Pac J Sports Med Arthrosc Rehabil Technol 4:9–20. https://doi.org/10.1016/j.asmart.2016.01.002
Cook JL, Purdam CR (2009) Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load-induced tendinopathy. Br J Sports Med 43:409–416. https://doi.org/10.1136/bjsm.2008.051193
Lagas IF, Tol JL, Weir A, Jonge S de, van Veldhoven PLJ, Bierma-Zeinstra SMA, Verhaar JAN, Vos R-J de (2023) One fifth of patients with Achilles tendinopathy have symptoms after 10 years: A prospective cohort study. J Sports Sci:1–9. https://doi.org/10.1080/02640414.2022.2163537
Kannus P, Józsa L (1991) Histopathological changes preceding spontaneous rupture of a tendon. A controlled study of 891 patients. J Bone Joint Surg Am 73:1507–1525
Steinmann S, Pfeifer CG, Brochhausen C, Docheva D (2020) Spectrum of Tendon Pathologies: Triggers, Trails and End-State. Int J Mol Sci 21. https://doi.org/10.3390/ijms21030844
Peters JA, Zwerver J, Diercks RL, Elferink-Gemser MT, van den Akker-Scheek I (2016) Preventive interventions for tendinopathy: A systematic review. J Sci Med Sport 19:205–211. https://doi.org/10.1016/j.jsams.2015.03.008
Wang S, Lyu B (2022) Are Current Prophylactic Programs Effective in Preventing Patellar Tendinopathy in Athletes and Recruits? A Meta-Analysis and Trial Sequential Analysis. Sports Health:19417381221121808. https://doi.org/10.1177/19417381221121808
Fredberg U, Stengaard-Pedersen K (2008) Chronic tendinopathy tissue pathology, pain mechanisms, and etiology with a special focus on inflammation. Scand J Med Sci Sports 18:3–15. https://doi.org/10.1111/j.1600-0838.2007.00746.x
Silbernagel KG, Hanlon S, Sprague A (2020) Current Clinical Concepts: Conservative Management of Achilles Tendinopathy. J Athl Train 55:438–447. https://doi.org/10.4085/1062-6050-356-19
Millar NL, Silbernagel KG, Thorborg K, Kirwan PD, Galatz LM, Abrams GD, Murrell GAC, McInnes IB, Rodeo SA (2021) Tendinopathy. Nat Rev Dis Primers 7:1. https://doi.org/10.1038/s41572-020-00234-1
Berg JM, Tymoczko JL, Stryer L (2013) Stryer Biochemie. Springer, Berlin Heidelberg, Berlin, Heidelberg
Juzenas S, Venkatesh G, Hübenthal M, Hoeppner MP, Du ZG, Paulsen M, Rosenstiel P, Senger P, Hofmann-Apitius M, Keller A, Kupcinskas L, Franke A, Hemmrich-Stanisak G (2017) A comprehensive, cell specific microRNA catalogue of human peripheral blood. Nucleic Acids Res 45:9290–9301. https://doi.org/10.1093/nar/gkx706
Ludwig N, Leidinger P, Becker K, Backes C, Fehlmann T, Pallasch C, Rheinheimer S, Meder B, Stähler C, Meese E, Keller A (2016) Distribution of miRNA expression across human tissues. Nucleic Acids Res 44:3865–3877. https://doi.org/10.1093/nar/gkw116
Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, Galas DJ, Wang K (2010) The microRNA spectrum in 12 body fluids. Clin Chem 56:1733–1741. https://doi.org/10.1373/clinchem.2010.147405
Cagney DN, Sul J, Huang RY, Ligon KL, Wen PY, Alexander BM (2018) The FDA NIH Biomarkers, EndpointS, and other Tools (BEST) resource in neuro-oncology. Neuro Oncol 20:1162–1172. https://doi.org/10.1093/neuonc/nox242
Mo W-Y, Cao S-Q (2022) MiR-29a-3p: a potential biomarker and therapeutic target in colorectal cancer. Clin Transl Oncol. https://doi.org/10.1007/s12094-022-02978-6
Balzano F, Deiana M, Dei Giudici S, Oggiano A, Baralla A, Pasella S, Mannu A, Pescatori M, Porcu B, Fanciulli G, Zinellu A, Carru C, Deiana L (2015) miRNA Stability in Frozen Plasma Samples. Molecules 20:19030–19040. https://doi.org/10.3390/molecules201019030
Swarbrick S, Wragg N, Ghosh S, Stolzing A (2019) Systematic Review of miRNA as Biomarkers in Alzheimer’s Disease. Mol Neurobiol 56:6156–6167. https://doi.org/10.1007/s12035-019-1500-y
Zailaie SA, Siddiqui JJ, Al Saadi RM, Anbari DM, Alomari S, A, Cupler EJ, (2022) Serum Based miRNA as a Diagnostic Biomarker for Multiple Sclerosis: a Systematic Review and Meta-Analysis. Immunol Invest 51:947–962. https://doi.org/10.1080/08820139.2021.1887888
Yan H, Ma F, Zhang Y, Wang C, Qiu D, Zhou K, Hua Y, Li Y (2017) miRNAs as biomarkers for diagnosis of heart failure: A systematic review and meta-analysis. Medicine (Baltimore) 96:e6825. https://doi.org/10.1097/MD.0000000000006825
Adhami M, Haghdoost AA, Sadeghi B, Malekpour Afshar R (2018) Candidate miRNAs in human breast cancer biomarkers: a systematic review. Breast Cancer 25:198–205. https://doi.org/10.1007/s12282-017-0814-8
Fabris L, Ceder Y, Chinnaiyan AM, Jenster GW, Sorensen KD, Tomlins S, Visakorpi T, Calin GA (2016) The Potential of MicroRNAs as Prostate Cancer Biomarkers. Eur Urol 70:312–322. https://doi.org/10.1016/j.eururo.2015.12.054
Zhong S, Golpon H, Zardo P, Borlak J (2021) miRNAs in lung cancer. A systematic review identifies predictive and prognostic miRNA candidates for precision medicine in lung cancer. Transl Res 230:164–196. https://doi.org/10.1016/j.trsl.2020.11.012
Liu Q, Zhu Y, Zhu W, Zhang G, Yang YP, Zhao C (2021) The role of MicroRNAs in tendon injury, repair, and related tissue engineering. Biomaterials 277:121083. https://doi.org/10.1016/j.biomaterials.2021.121083
Ding L, Wang M, Qin S, Xu L (2021) The Roles of MicroRNAs in Tendon Healing and Regeneration. Front Cell Dev Biol 9:687117. https://doi.org/10.3389/fcell.2021.687117
Dubin JA, Greenberg DR, Iglinski-Benjamin KC, Abrams GD (2018) Effect of micro-RNA on tenocytes and tendon-related gene expression: A systematic review. J Orthop Res 36:2823–2829. https://doi.org/10.1002/jor.24064
Giordano L, Della Porta G, Peretti GM, Maffulli N (2020) Therapeutic potential of microRNA in tendon injuries. Br Med Bull 133:79–94. https://doi.org/10.1093/bmb/ldaa002
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71. https://doi.org/10.1136/bmj.n71
Centre for Reviews and Dissemination (2009) CRD’s guidance for undertaking reviews in healthcare, 3rd edn. Systematic reviews. York Publ, Services, York
Ilaltdinov AW, Gong Y, Leong DJ, Gruson KI, Zheng D, Fung DT, Sun L, Sun HB (2021) Advances in the development of gene therapy, noncoding RNA, and exosome-based treatments for tendinopathy. Ann N Y Acad Sci 1490:3–12. https://doi.org/10.1111/nyas.14382
Montero JA, Lorda-Diez CI, Hurlé JM (2012) Regenerative medicine and connective tissues: cartilage versus tendon. J Tissue Eng Regen Med 6:337–347. https://doi.org/10.1002/term.436
Thankam FG, Boosani CS, Dilisio MF, Agrawal DK (2019) Epigenetic mechanisms and implications in tendon inflammation (Review). Int J Mol Med 43:3–14. https://doi.org/10.3892/ijmm.2018.3961
Scottish Intercollegiate Guidelines NetworkScottish Intercollegiate Guidelines Network (SIGN)Scottish Intercollegiate Guidelines Network (SIGN)Scottish Intercollegiate Guidelines Network (SIGN) (2020). https://www.sign.ac.uk/. Accessed 22 Feb 2022
Asker M, Brooke HL, Waldén M, Tranaeus U, Johansson F, Skillgate E, Holm LW (2018) Risk factors for, and prevention of, shoulder injuries in overhead sports: a systematic review with best-evidence synthesis. Br J Sports Med 52:1312–1319. https://doi.org/10.1136/bjsports-2017-098254
Thankam FG, Boosani CS, Dilisio MF, Agrawal DK (2018) MicroRNAs associated with inflammation in shoulder tendinopathy and glenohumeral arthritis. Mol Cell Biochem 437:81–97. https://doi.org/10.1007/s11010-017-3097-7
Plachel F, Heuberer P, Gehwolf R, Frank J, Tempfer H, Lehner C, Weissenbacher N, Wagner A, Weigl M, Moroder P, Hackl M, Traweger A (2020) MicroRNA Profiling Reveals Distinct Signatures in Degenerative Rotator Cuff Pathologies. J Orthop Res 38:202–211. https://doi.org/10.1002/jor.24473
Ge Z, Tang H, Lyu J, Zhou B, Yang M, Tang K, Chen W (2020) Conjoint analysis of lncRNA and mRNA expression in rotator cuff tendinopathy. Ann Transl Med 8:335. https://doi.org/10.21037/atm.2020.02.149
Hall KE, Sarkissian EJ, Sharpe O, Robinson WH, Abrams GD (2019) Identification of differentially expressed micro-RNA in rotator cuff tendinopathy. Muscle Ligaments and Tendons J 08:8. https://doi.org/10.32098/mltj.01.2018.02
Leal MF, Caires Dos Santos L, Martins de Oliveira A, Santoro Belangero P, Antônio Figueiredo E, Cohen C, de Seixas Alves F, Hiromi Yanaguizawa W, Vicente Andreoli C, de Castro Pochini A, Ejnisman B, Cardoso Smith M, de Seixas Alves MT, Cohen M (2017) Epigenetic regulation of metalloproteinases and their inhibitors in rotator cuff tears. PLoS One 12:e0184141. https://doi.org/10.1371/journal.pone.0184141
Abrahams Y, Laguette M-J, Prince S, Collins M (2013) Polymorphisms within the COL5A1 3’-UTR that alters mRNA structure and the MIR608 gene are associated with Achilles tendinopathy. Ann Hum Genet 77:204–214. https://doi.org/10.1111/ahg.12013
Brown KL, Seale KB, El Khoury LY, Posthumus M, Ribbans WJ, Raleigh SM, Collins M, September AV (2017) Polymorphisms within the COL5A1 gene and regulators of the extracellular matrix modify the risk of Achilles tendon pathology in a British case-control study. J Sports Sci 35:1475–1483. https://doi.org/10.1080/02640414.2016.1221524
Feng W, Jin Q, Ming-Yu Y, Yang H, Xu T, You-Xing S, Xu-Ting B, Wan C, Yun-Jiao W, Huan W, Ai-Ning Y, Yan L, Hong T, Pan H, Mi-Duo M, Gang H, Mei Z, Xia K, Kang-Lai T (2021) MiR-6924–5p-rich exosomes derived from genetically modified Scleraxis-overexpressing PDGFRα(+) BMMSCs as novel nanotherapeutics for treating osteolysis during tendon-bone healing and improving healing strength. Biomaterials 279:121242. https://doi.org/10.1016/j.biomaterials.2021.121242
GeShresthaLiuWuCheng HACPB (2018) MicroRNA 148a–3p promotes Thrombospondin-4 expression and enhances angiogenesis during tendinopathy development by inhibiting Krüppel-like factor 6. Biochem Biophys Res Commun 502:276–282. https://doi.org/10.1016/j.bbrc.2018.05.167
Han W, Wang B, Liu J, Chen L (2017) The p16/miR-217/EGR1 pathway modulates age-related tenogenic differentiation in tendon stem/progenitor cells. Acta Biochim Biophys Sin (Shanghai) 49:1015–1021. https://doi.org/10.1093/abbs/gmx104
Lu Y-F, Liu Y, Fu W-M, Xu J, Wang B, Sun Y-X, Wu T-Y, Xu L-L, Chan K-M, Zhang J-F, Li G (2017) Long noncoding RNA H19 accelerates tenogenic differentiation and promotes tendon healing through targeting miR-29b-3p and activating TGF-β1 signaling. FASEB J 31:954–964. https://doi.org/10.1096/fj.201600722R
Millar NL, Gilchrist DS, Akbar M, Reilly JH, Kerr SC, Campbell AL, Murrell GAC, Liew FY, Kurowska-Stolarska M, McInnes IB (2015) MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease. Nat Commun 6:6774. https://doi.org/10.1038/ncomms7774
Peffers MJ, Fang Y, Cheung K, Wei TKJ, Clegg PD, Birch HL (2015) Transcriptome analysis of ageing in uninjured human Achilles tendon. Arthritis Res Ther 17:33. https://doi.org/10.1186/s13075-015-0544-2
Sun Y, Chen H, Ye H, Liang W, Lam K-K, Cheng B, Lu Y, Jiang C (2020) Nudt21-mediated alternative polyadenylation of HMGA2 3’-UTR impairs stemness of human tendon stem cell. Aging (Albany NY) 12:18436–18452. https://doi.org/10.18632/aging.103771
Thankam FG, Boosani CS, Dilisio MF, Dietz NE, Agrawal DK (2016) MicroRNAs Associated with Shoulder Tendon Matrisome Disorganization in Glenohumeral Arthritis. PLoS One 11:e0168077. https://doi.org/10.1371/journal.pone.0168077
Thankam FG, Boosani CS, Dilisio MF, Gross RM, Agrawal DK (2019) Genes interconnecting AMPK and TREM-1 and associated microRNAs in rotator cuff tendon injury. Mol Cell Biochem 454:97–109. https://doi.org/10.1007/s11010-018-3456-z
Wang B, Guo J, Feng L, Suen C-W, Fu W-M, Zhang J-F, Li G (2016) MiR124 suppresses collagen formation of human tendon derived stem cells through targeting egr1. Exp Cell Res 347:360–366. https://doi.org/10.1016/j.yexcr.2016.08.018
Xiao M, Iglinski-Benjamin KC, Sharpe O, Robinson WH, Abrams GD (2019) Exogenous micro-RNA and antagomir modulate osteogenic gene expression in tenocytes. Exp Cell Res 378:119–123. https://doi.org/10.1016/j.yexcr.2019.03.008
Cai X, Cai M, Lou L (2015) Identification of differentially expressed genes and small molecule drugs for the treatment of tendinopathy using microarray analysis. Mol Med Rep 11:3047–3054. https://doi.org/10.3892/mmr.2014.3081
Chen L, Liu J, Tao X, Wang G, Wang Q, Liu X (2015) The role of Pin1 protein in aging of human tendon stem/progenitor cells. Biochem Biophys Res Commun 464:487–492. https://doi.org/10.1016/j.bbrc.2015.06.163
Hu J, Liao H, Ma Z, Chen H, Huang Z, Zhang Y, Yu M, Chen Y, Xu J (2016) Focal Adhesion Kinase Signaling Mediated the Enhancement of Osteogenesis of Human Mesenchymal Stem Cells Induced by Extracorporeal Shockwave. Sci Rep 6:20875. https://doi.org/10.1038/srep20875
Poulsen RC, Knowles HJ, Carr AJ, Hulley PA (2014) Cell differentiation versus cell death: extracellular glucose is a key determinant of cell fate following oxidative stress exposure. Cell Death Dis 5:e1074. https://doi.org/10.1038/cddis.2014.52
Zhao T, Meng W, Chin Y, Gao L, Yang X, Sun S, Pan X, He L (2021) Identification of miR-25-3p as a tumor biomarker: Regulation of cellular functions via TOB1 in breast cancer. Mol Med Rep 23:406. https://doi.org/10.3892/mmr.2021.12045
Fujiwara T, Uotani K, Yoshida A, Morita T, Nezu Y, Kobayashi E, Yoshida A, Uehara T, Omori T, Sugiu K, Komatsubara T, Takeda K, Kunisada T, Kawamura M, Kawai A, Ochiya T, Ozaki T (2017) Clinical significance of circulating miR-25–3p as a novel diagnostic and prognostic biomarker in osteosarcoma. Oncotarget 8:33375–33392. https://doi.org/10.18632/oncotarget.16498
Gross AC, Cam H, Phelps DA, Saraf AJ, Bid HK, Cam M, London CA, Winget SA, Arnold MA, Brandolini L, Mo X, Hinckley JM, Houghton PJ, Roberts RD (2018) IL-6 and CXCL8 mediate osteosarcoma-lung interactions critical to metastasis. JCI Insight 3. https://doi.org/10.1172/jci.insight.99791
Knüpfer H, Preiss R (2007) Significance of interleukin-6 (IL-6) in breast cancer (review). Breast Cancer Res Treat 102:129–135. https://doi.org/10.1007/s10549-006-9328-3
Legerlotz K, Jones ER, Screen HRC, Riley GP (2012) Increased expression of IL-6 family members in tendon pathology. Rheumatology (Oxford) 51:1161–1165. https://doi.org/10.1093/rheumatology/kes002
Ndzi EN, Nkenfou CN, Mekue LM, Zentilin L, Tamgue O, Pefura EWY, Kuiaté J-R, Giacca M, Ndjolo A (2019) MicroRNA hsa-miR-29a-3p is a plasma biomarker for the differential diagnosis and monitoring of tuberculosis. Tuberculosis (Edinb) 114:69–76. https://doi.org/10.1016/j.tube.2018.12.001
Boni FG, Hamdi I, Koundi LM, Shrestha K, Xie J (2022) Cytokine storm in tuberculosis and IL-6 involvement. Infect Genet Evol 97:105166. https://doi.org/10.1016/j.meegid.2021.105166
Briukhovetska D, Dörr J, Endres S, Libby P, Dinarello CA, Kobold S (2021) Interleukins in cancer: from biology to therapy. Nat Rev Cancer 21:481–499. https://doi.org/10.1038/s41568-021-00363-z
Wang Z, Huang C, Zhao C, Zhang H, Zhen Z, Xu D (2021) Knockdown of LINC01385 inhibits osteoarthritis progression by modulating the microRNA-140-3p/TLR4 axis. Exp Ther Med 22:1244. https://doi.org/10.3892/etm.2021.10679
Ellis I, Schnabel LV, Berglund AK (2022) Defining the Profile: Characterizing Cytokines in Tendon Injury to Improve Clinical Therapy. J Immunol Regen Med 16:100059. https://doi.org/10.1016/j.regen.2022.100059
Aigner T, Soeder S, Haag J (2006) IL-1beta and BMPs--interactive players of cartilage matrix degradation and regeneration. Eur Cell Mater 12:49–56; discussion 56. https://doi.org/10.22203/eCM.v012a06
Gu C, Hou C, Zhang S (2020) miR-425-5p improves inflammation and septic liver damage through negatively regulating the RIP1-mediated necroptosis. Inflamm Res 69:299–308. https://doi.org/10.1007/s00011-020-01321-5
The study was funded by the Open Access Publishing Fund of Leipzig University supported by the German Research Foundation within the program Open Access Publication Funding. The authors´ acknowledge support from Leipzig University for Open Access Publishing.
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Schmid, T., Wegener, F., Hotfiel, T. et al. Moderate evidence exists for four microRNAs as potential biomarkers for tendinopathies and degenerative tendon ruptures at the upper extremity in elderly patients: conclusion of a systematic review with best-evidence synthesis. J EXP ORTOP 10, 81 (2023). https://doi.org/10.1186/s40634-023-00645-5
- Circulating RNA
- Connective tissue
- Tendon pathology
- Shoulder pathology