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Biochemical markers of postsurgical knee arthrofibrosis: A systematic review
∗Corresponding author: Phillip B. Wyatt. wyattpb2@vcu.edu
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Received: ,
Accepted: ,
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.
Abstract
Abstract
Postsurgical knee arthrofibrosis is a common complication associated with pain and limited range of motion. Although the mechanism is unclear, many biochemical and genetic markers have been identified within arthrofibrotic knees. The purpose of this systematic review is to synthesize the many biochemical and genetic markers that have been associated with surgery-induced knee arthrofibrosis in order to better guide future therapeutic endeavors.
A thorough search of literature was conducted on April 27, 2022. Seventeen studies met inclusion criteria for this systematic review. Inclusion criteria for this study were as follows: title or abstract discussed biochemical and genetic markers associated with postoperative knee arthrofibrosis, study design included human and/or animal subjects.
A wide variety of genetic biomarkers (mRNA), proteins/enzymes, and cytokines were identified in both animal models and human subjects with postsurgical knee arthrofibrosis. These included various extracellular matrix-encoding mRNA sequences, matrix metalloproteinases, proteins and mRNA sequences involved in Transforming Growth Factor-β signaling, and interleukin-family cytokines to name just a few.
There are many biomarkers found in postsurgical arthrofibrotic knees. TGF-β, and mRNA/proteins that participate in TGF-β signaling (i.e., LOX, SERPINE1, PAI-1/Akt/mTOR, BMP-2), appear to be particularly common. Future comparative studies should aim to determine which of these are most relevant, and therefore, worthwhile therapeutic targets.
Keywords
Knee
Postoperative arthrofibrosis
Biochemical markers
Genetic markers
Postoperative complication
Knee surgery
1 Introduction
Postsurgical knee arthrofibrosis is a common complication after procedures such as total knee arthroplasty (TKA) and anterior cruciate ligament reconstruction.1,2 It is characterized by early and prolonged limitations in range of motion and is one of the leading causes of TKA failure in the United States.2 Although the pathogenesis of arthrofibrosis is largely unclear, it is thought to be mediated by myofibroblasts peaking 2 weeks after trauma, but differential gene expression can occur very soon after an injury or surgery.3
The current body of literature regarding the biochemical markers of arthrofibrosis in the knee is heterogenous. However, to the authors’ knowledge, no previous systematic review has been published that synthesizes currently identified biochemical markers of postsurgical arthrofibrosis in the knee. Previous studies have attempted to treat arthrofibrosis with varying success in animal models and human myofibroblast cultures with biochemical targets such as Interleukin-1 receptor 1 and proteins along the mTOR signaling pathway.4,5 Knowledge of the most-associated biomarkers will help guide future research and targeted therapeutics for this cumbersome and costly postoperative complication.
This systematic review serves to synthesize the current body of literature regarding knee arthrofibrosis in animals and humans by identifying the (1) genetic biomarkers, (2) proteins/enzymes, and (3) cytokines that are most likely associated with the development of postsurgical knee arthrofibrosis.
2 Methods
This is a systematic review of studies that have investigated biochemical and genetic markers of postoperative knee arthrofibrosis published prior to April 27, 2022. Our study used the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for reporting systematic reviews.
2.1 Search strategy
One author (J.C.) searched the Pubmed/Medline, Cochrane, CINAHL, and Embase (OVID) databases on April 27, 2022, using the following search string: (“arthrofibrosis” OR “knee + fibrosis”) AND (“biomarker(s)” OR “molecules” OR “molecular” OR “RNA” OR “pathway(s)”).
2.2 Screening, inclusion/exclusion criteria
Duplicates and papers written in languages other than English were excluded. Two authors (P.W., J.S.) independently screened all the articles using this review's inclusion and exclusion criteria. Each study was reviewed first by title and abstract, then by full text if more detail was required to make the decision of inclusion. Inclusion criteria for this study were as follows: title or abstract discussed biochemical and genetic markers associated with postoperative knee arthrofibrosis, study design included human and/or animal subjects. Exclusion criteria were as follows: studies that did not discuss or investigate biochemical and genetic markers of postoperative knee arthrofibrosis, studies that were case report/series.
2.3 Data extraction
Data were extracted by one author (P.W.). The data that were systematically extracted included salient findings regarding specific biochemical and/or genetic markers associated with postoperative knee arthrofibrosis.
After duplicates were removed, the initial search revealed 246 articles. Through title and abstract screening, 182 of these articles were excluded. This left 64 articles. Full-text versions of these articles were then assessed for eligibility. Of these, 17 articles fully met inclusion criteria without any exclusion criteria and were, therefore, decided to be included in this systematic review. This process is illustrated in (Fig. 1).
2.4 Outcomes of interest
All biochemical and genetic markers (including RNA) were considered of interest in this review.
2.5 Characteristics of included studies
The included studies were all published prior to April 27, 2022. Six of these studies used animal subjects, nine used human subjects, and two of them included both human and animal groups. Of the 17 included studies, five were randomized control trials,6–10 while the rest were observational studies of various designs: prospective cohort (5), case-control (4), and comparative cross-sectional studies (2). All five of the randomized control trials used rabbits or rats as subjects.
2.6 Methodological quality assessment
The Newcastle-Ottawa Quality Assessment Scale (NOS) was chosen to assess the risk of bias among the human studies, all of which were observational. Using the NOS, one author (P.W.) determined that five studies were at a low risk of bias,11–15 one study had a medium risk of bias,16 and two had a high risk of bias.17,18
The studies using animal subjects were assessed using the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE), which is a version of the Risk of Bias-2 (Cochrane) tool and adapted for animal studies. Using the SYRCLE tool, one author (P.W.) determined that all the studies involving animal subjects were at medium-to-high risk of bias with no study meeting more than 5 of the 10 listed criteria in the SYRCLE tool.
3 Results
The most common location of tissue sample was the synovial tissue with five studies using posterior knee synovial tissue6,7,13,19,20 and four studies using unspecified knee synovial tissue from an unspecified location.11,12,18,21 One study obtained samples from both anterior and posterior portions of the knee synovial tissue, suprapatellar pouch, and cancellous bone.20 Two studies obtained samples from synovial fluid,14,17 and one of them also obtained blood plasma samples for comparison.14 One study obtained samples from the anterior and intercondylar knee compartment.16 Lastly, one study obtained samples from the location of surgically-induced bone lesions.10 The salient biomarkers found in each study, origin of the samples obtained, and type of subjects are summarized in Table 1 Salient biomarkers in Table 1 were defined as biomarkers that were both reported and thoroughly discussed by the original study authors.
| Study Author(s) | Biomarkers Associated with Postoperative Knee Arthrofibrosis | Subjects | Origin of Samples |
| Tibbo et al. (2020)6 | ACTA2 mRNA | Rats | Posterior knee synovial tissue |
| Steplewski et al. (2016)33 | Heat Shock Protein 47, alpha subunit of Prolyl 4-Hydroxylase | Rabbits | Posterior knee synovial tissue |
| Owen et al. (2022)7 | MMP-28 mRNA | Rats | Posterior knee synovial tissue |
| Sun et al. (2021)8 | P13K, Akt, mTOR | Rabbits | Intraarticular lesions on the femoral condyles |
| Xia et al. (2021)9 | IL-1B, IL-6, HOX mRNA | Mice | Anterior and posterior knee synovial tissue, suprapatellar pouch tissue, and cancellous bone |
| Morrey et al. (2017)19 | IL-1B, FGF9, ADH1, CXCR2, IL6, IL8, NP3A mRNA.CXCR2, IL6, and IL8 were increased the greatest. | Rabbits | Posterior knee synovial tissue |
| Bosch et al. (2001)16 | CD25 T cells, CD4+ helper T cells, and Th1 and Th2 cells. More Th1 than Th2 cells; CD80/CD28 (costimulatory signal in T-cell activation) | Humans | Anterior and intercondylar knee compartment |
| Pfitzner et al. (2012)17 | BMP-2 | Humans | Synovial fluid |
| Liu et al. (2020)10 | P13K, Akt, mTOR | Rabbits (compared to human fibroblasts in vitro) | At the location of surgically-induced bone lesions (in rabbits) |
| Bernstein et al. (2020)18 | Xylosyltransferase-1 | Humans | Unspecified tissues from the knee joint |
| Faust et al. (2015)11 | Xylosyltransferase activity, alpha-smooth muscle actin, and Xylosyltransferase-1ACTA2 mRNA | Humans | Synovial Tissue |
| Chen et al. (2021)12 | TGF-B Receptor 1 | Humans and Rabbits | Synovial tissue of humans and rats |
| Mayr et al. (2019)21 | CD-68 positive cells, alpha-smooth muscle actin, beta-catenin, and BMP-2 | Humans | Synovial tissue |
| Bayram et al. (2020)13 | COL1A1, COL3A1and COL6A1, LOX, SERPINE1 mRNA | Humans | Posterior knee synovial tissue |
| Malahias et al. (2020)14 | Eotaxin3, IL-5, IL12_23p40, IP10, VEGF, IL-7, IL-12p70, IL-16, IL-17a | Humans | Knee synovial fluid & blood plasma |
| Freeman et al. (2009)15 | Myeloperoxidase | Humans | Knee synovial tissue |
| Mann et al. (2019)20 | Genetic expression of Matrix Metalloproteinases (MMPs), A Disintegrin and Metalloproteinases with Thrombospondin (ADAMTS) and Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) | Humans | Suprapatellar pouch tissue |
3.1 Genetic markers of arthrofibrosis
A total of eighteen genetic biomarkers were identified in subjects with postoperative arthrofibrosis of the knee. Of these genetic markers, only three were identified in more than one study: IL-1B, IL-69,20, and ACTA2.6,11 The genes IL-1B and IL-6 both encode interleukins of the same name. The ACTA2 gene encodes alpha-smooth muscle actin which is a component of the extracellular matrix. In one study, the gene encoding IL-6 appeared to be increased more than the gene encoding IL-1B in the presence of arthrofibrosis.20 Morrey et al. also found that in addition to genes encoding IL-6, the genes encoding CXCR2 and IL-8 were the most dramatically increased in the setting of arthrofibrosis in rabbits. RNA sequencing in another study identified fourteen different types of collagen-encoding genes in human arthrofibrotic knee synovial joint tissue samples, the combination of which could be unique to the arthrofibrotic knee.13 These authors also identified upregulated expression of LOX in the arthrofibrotic group (compared to non-arthrofibrotic groups), which encodes an extracellular amine oxidase involved in collagen crosslinking, and SERPINE1, which is known to conserve scarring, to be preferentially expressed in arthrofibrotic human synovial tissue.13
Genetic transcription of Matrix Metalloproteinases (MMP), which are known to play a role in extracellular matrix remodeling, was found to be elevated in two animal studies.7,22 However, the specific enzyme within the MMP family that plays the greatest role in arthrofibrosis remains unclear. Matrix Metalloproteinase-28 (MMP-28) which encodes MMP-28 was found to be preferentially expressed in arthrofibrotic knee joints in rats.7 Additionally, the HOX antisense RNA (HOTAIR) was found to be increased in arthrofibrotic joints in mice when compared to a control group.9HOX (HOTAIR) controls transcription of multiple extracellular matrix proteins and enzymes, including MMP-2, MMP-3, MMP-3, MMP-12, MMP-13, MMP-14 among others. Interestingly, MMP-28 is not one of the Matrix Metalloproteinases whose transcription is known to be controlled by the HOX gene.9 Matrix Metalloproteinase-28 has been previously associated with post-myocardial infarction left ventricular rupture in mice23 and hypertrophic scar formation in humans,24 but a mechanism for MMP-28's role in arthrofibrosis has not yet been defined.
3.2 Protein and enzymatic markers of arthrofibrosis
Among the various proteins and enzymes identified, alpha smooth muscle actin,11,21 xylosyltransferase I (XT-1),11,18 and Bone Morphogenic Protein-2 (BMP-2)17,21 were identified in multiple studies. As expected from the genetic studies reported above, Matrix Metalloproteinases (MMP) appeared to be associated with postsurgical knee arthrofibrosis in rats and humans.7,22 Additionally, proteins such as CD25, CD4, CD80, CD20 (T-lymphocyte markers), and CD68 (a marker commonly found on cells of macrophages and other cells of monocytic origin) were identified in synovial tissue of fibrotic joints, indicating that lymphocytic and histochemical changes likely play a role in the pathogenesis of arthrofibrosis.16,21
Compared to a control group of fibroblasts from non-arthrofibrotic human knee joints with artificially-induced inflammation via TGF-B (a known mediator of fibrosis), fibroblasts from knee joints with known surgically-induced arthrofibrosis demonstrated an increased expression in XT-1.11 This finding was verified by another cross-sectional study that found elevated XT-1 expression in arthrofibrotic human knee synovial tissue compared to that of healthy controls.18 Therefore, biomarkers of surgically-induced arthrofibrosis may be unique from other methods of arthrofibrosis induction.
Signaling pathway proteins P13K, AKT, and mTOR were found to be decreased in certain therapeutic interventions that aimed to reduce arthrofibrosis via induction myofibroblast apoptotic mechanisms. The P13K/ADT/mTOR pathway is a known pathway involved in cell cycle regulation. One study found that Homoharringtinone (an anti-leukemia drug) decreased development of arthrofibrosis in rabbits after surgery via a decrease in P13K/AKT/mTOR signaling.8 This reduction in arthrofibrosis development was accompanied by a decrease in P13K, AKT, and mTOR protein levels. Another study found that Everolimus, an mTOR inhibitor typically indicated for rejection prophylaxis in the setting of organ transplant and some neoplasms, decreased these same protein levels in postoperative arthrofibrotic knee joints in rabbits and they also found an associated increase in fibroblast apoptosis in isolated human fibroblasts when exposed to the drug.10 This suggests that P13K/AKT/mTOR pathway signaling could play a large role in the pathogenesis of arthrofibrosis by prolonging the life span of myofibroblasts. Therefore, proteins along this pathway could serve as future therapeutic targets for postoperative arthrofibrosis.
Markers related to the Transforming Growth Factor family of proteins were elevated across multiple studies. The receptor for Transforming Growth Factor-β1 (TGF-β1) was found to be elevated in both rats with surgically induced arthrofibrosis and humans who had developed arthrofibrosis after a total knee arthroplasty when compared to a healthy control.12 Bone Morphogenic Protein-2 (BMP-2), a member of the TGF-β superfamily, was found to be elevated in synovial fluid of patients with postoperative arthrofibrosis of the knee17 and within perivascular portions of the synovial tissue on immunohistochemical stain.21 Furthermore, BMP-2 concentrations in synovial tissue were positively correlated to synovial tissue density.17
3.3 Cytokines associated with arthrofibrosis
Cytokines play a role in the development of arthrofibrosis in both animal and human models. The most common cytokines that were identified among the studies were IL-1B and IL-6. Morrey et al. found that IL-6 and IL-8 were the most dramatically increased in rabbits after surgically-induced arthrofibrosis.20 One prospective cohort study identified many cytokines that were significantly higher in the plasma of patients that would go on to develop arthrofibrosis after a total knee arthroplasty: Eotaxin3, IL-5, IL12_23p40, IP10, VEGF, IL-7, IL-12p70, IL-16, IL-17a. These were observed at postoperative days 1 and/or 2, indicating that serum cytokine levels may be most noticeable in the immediate postoperative period and may serve as predictors of postoperative arthrofibrosis development.14
4 Discussion
Early identification of genetic and molecular markers of arthrofibrosis would help guide the development of effective therapeutic agents. However, the current body of literature is heterogeneous, with various study designs, non-standardized methods, and a wide variety of findings. The findings of this systematic review indicate the need for future, better-controlled animal and human studies that define reliable, early biochemical predictors of knee arthrofibrosis in order to assess risk and development treatment options for patients undergoing knee surgery. This review highlights several noteworthy biochemical markers that have been identified thus far in currently published research.
This review is primarily limited by the heterogeneity of included studies and the high risk of bias in multiple included studies. The various research models and methods of marker detection make it difficult to strongly conclude which markers are most prevalent, let alone clinically relevant. Additionally, this study did not include a meta-analysis as this was not feasible. Despite these limitations, this review was able to identify some relevant markers that may guide future research and development of therapeutic options for treating postoperative knee arthrofibrosis.
Genes such as LOX and SERPINE1 appear to be preferentially expressed in arthrofibrotic knee synovial tissue in humans. LOX has previously been shown to contribute to pulmonary fibrosis,25 but its role in arthrofibrosis is unclear and will require further research. SERPINE1 encodes for plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor that contributes to extracellular matrix remodeling. Signaling from Transforming Growth Factor-β (TGF-β) increases production of PAI-1 via an increase in SERPINE1 expression.26 Therefore, interruption of TGF-β signaling may a suitable therapeutic target upstream from SERPINE1 to reduce proliferation of fibrotic tissue in knee joints. Fig. 2 illustrates inflammatory signaling through TGF-β and other molecules, leading to tissue fibrosis.27 The interplay of LOX, PAI-1, and TGF-β signaling in fibrogenesis is illustrated in Fig. 3, adopted from Chen et al.28
Transforming Growth Factor-β1 is a well-known inducer of fibrosis in other tissue such as lung and liver parenchyma via Smad signaling.29 Smad signaling gives rise to most of the profibrotic effects associated with fibrosis, including proliferation and transcription of extracellular matrix elements (i.e., SERPINE1 transcription). Prior studies have successfully induced knee arthrofibrosis in rats30 and in human myofibroblasts with administration of TGF-β1.31 This, combined with our findings suggest that proteins from the TGF-β family, particularly TGF-β112 and BMP-2,17,21 should be a target of future research in postoperative knee arthrofibrosis.
Autophagy-promoting cell signaling via the P13K/AKT/mTOR proteins has been associated with both renal fibrosis and arthrofibrosis in prior studies.5,32 The result of cell autophagy is release of the cell's degraded contents into the extracellular matrix. The mechanism behind how this causes arthrofibrosis is unclear. However, it is possible that the release of the autophagocytosed myofibroblast's contents creates an inflammatory response in the synovial tissue of the post-surgical knee. Then, for reasons unknown, certain patients mount an exaggerated and prolonged inflammatory response, leading to fibrosis of the joint. By this logic, the use of medications such as Everolimus and Homoharringtinone that suppress mTOR signaling (and therefore may suppress myofibroblast autophagy) may be beneficial in the setting of post-surgical arthrofibrosis.
Fibrosis of the knee joint appears to contain unique extracellular matrix proteins and enzymes compared to other fibrotic tissues in the body. Collagen is an integral component of the extracellular matrix and makes up a significant proportion of the extracellular matrix. Previous research has shown COL1A1, COL3A1, COL6A1, COL7A1 and COL8A1 are involved in the process of fibrosis outside of synovial joints (liver, lung).33–35 Genes encoding these collagens were also found in Bayram et al.‘s paper, but the nine other collagen-encoding genes found by the authors (COL5A3, COL13A1, COL4A1, COL2A1, COL5A1, COL11A1, COL11A2, COL12A1, COL10A1) illustrate that arthrofibrosis of the knee involves a unique combination of collagens. This demonstrates a need for future research to assess the importance of each type in the pathogenesis of arthrofibrosis and their potential as a target of future therapeutics.
Alpha-smooth muscle actin, and evidence of its transcription (ACTA2 gene), was identified as a component of fibrotic synovial tissue in several studies.6,11,21 This is not surprising as alpha-smooth muscle actin is a well-known component of the extracellular matrix. This makes it a tempting option for future therapeutics. However, mutations in ACTA2 are known to cause aortic aneurysms and dissections.36 Therefore, developing a therapeutic agent targeting alpha-smooth muscle actin or its transcription could be problematic.
Interleukin family cytokines have been shown to play a role in the development of fibrosis in the liver in previous studies. For example, inhibition of IL-13 has been found to decrease hepatic fibrosis in multiple experimental models.37,38 In this review, postoperative serum levels and transcription of IL-1B, IL-6, IL-8, and cognate receptor CXCR2 appeared to be elevated early in the process of arthrofibrosis in human postsurgical studies. Given that the levels of these markers peaked between 12 and 24 h postoperatively, future studies regarding therapeutics should focus on early postoperative evaluation of serum cytokine levels. Further research is needed to determine whether IL-1B, IL-6, IL-8, and CXCR2 may be suitable therapeutic targets.
5 Conclusion
The pathogenesis of postoperative knee arthrofibrosis remains unclear. Biochemical marker identification is the first step in developing therapeutics aimed to prevent and treat postoperative knee arthrofibrosis. This review identifies several genetic and molecular biomarkers within the existing body of literature. Future studies are needed to help identify the most reliable and relevant biomarkers of arthrofibrosis.
Funding/sponsorship
This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.
Informed consent
Not applicable.
Institutional ethical committee approval
Not applicable.
Author statement
Phillip Wyatt: Writing - Original draft preparation, conceptualization, methodology, writing – reviewing and editing, investigation, data curation, formal analysis, visualization James Satalich: Writing-reviewing and editing, conceptualization, project administration John Cyrus: Methodology, data curation, formal analysis Conor O'Neill: writing – reviewing and editing, conceptualization Robert O'Connell: writing – reviewing and editing, conceptualization.
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