Some medications already in use for other conditions may have therapeutic potential for arthrofibrosis. Liu et al.303 found that in rabbits the topical application of daidzein to exposed tissue during surgery reduced fibroblast density, collagen formation and adhesions. As a common complication following total knee arthroplasty (TKA), this benign-appearing connective tissue hyperplasia can cause significant disability among patients because the concomitant knee pain and restricted range of motion severely hinder postoperative rehabilitation, clinical . 7, 14811485 (2014). & Bayat, A. 9, 133 (2017). Am. The debilitating disease, which affects more than 20 percent of adults in the United States, is the leading cause of disability in the nation. Cancer 134, 10341044 (2014). This review focuses on pathogenesis of sterile arthrofibrosis and therapeutic treatments. Sports Traumatol. Jonathan Cluett, MD, is board-certified in orthopedic surgery. patellar (kneecap) immobility. 1). Pathol. Introduction. Sports Med. J. Pathol. 19, 704712 (2013). J. Kidney Int. USA 106, 1451814523 (2009). Usher, K.M., Zhu, S., Mavropalias, G. et al. inability to fully straighten (extension) the knee. 36, 29492955 (2018). However, current research into the pathogenesis of fibrosis in organs now informs the understanding of arthrofibrosis. Motion-limiting arthrofibrosis has been described in numerous joints, including the knee [1-4], ankle [5,6], shoulder [7-10], and elbow [11,12]. This could potentially stop the pathological cascade of dysregulation and positive feedback that results in permanent active fibrosis,214 while also preventing damage to joint structures such as cartilage and ligaments that occurs with tissue contraction and altered biomechanics. Serhan, C. N. et al. During the evaluation, the patient was placed on a recumbent bike for 10 minutes and while getting off, she had a problem clearing the right leg over the equipment to dismount and fell. & McKinsey, T. A. Epigenetics in cardiac fibrosis: emphasis on inflammation and fibroblast activation. & Hwang, S. W. Resolvins: endogenously-generated potent painkilling substances and their therapeutic perspectives. Local cytokine profiles in knee osteoarthritis: elevated synovial fluid interleukin-15 differentiates early from end-stage disease. 27, 200215 (2015). The KNEEguru, http://www.kneeguru.co.uk/KNEEtalk/ (1997). Ruppert, M. et al. Exp. 138, 9841010 (2016). Rev. Orthop. A detailed explanation of all of these factors is beyond the scope of this review; therefore, we present a summary of the important cytokines and mediators involved in the condition. Liver Dis. New therapeutic targets include epigenetic modifications, TGF- and its downstream signalling, IL-1, NLRP3 inflammasomes, mast cells, substance P and hypoxia-inducible factor-1. TNF- has pleiotropic effects, and its role in organ fibrosis remains controversial.285,286 In addition, it may have different effects in different organs.285 The importance of TNF- in established fibrosis remains to be clarified, and further research is required to understand the effectiveness of TNF- antibodies as a therapeutic agent for treating fibrosis. Surg. This review highlights current progress in understanding the pathogenesis of sterile arthrofibrosis, focusing on arthrofibrosis of the knee to illustrate the condition. A rat model of fatty liver disease showed that TNF- antibody treatment reduced inflammation and fibrosis, as well as serum TGF- in experimental models.285,288. Rev. As mentioned previously, this fits with views expressed recently that rehabilitation should be progressed conservatively, and based on the inflammatory response it provokes.12,328. Gastroenterology 147, 13781392 (2014). 119, 13261336 (2018). PubMed J. 38, 566571 (2008). Yoshida, S. et al. Rheumatology 54, 19541963 (2015). Immun. J. Leukoc. Physiol. 20, 1477814786 (2014). Soc. . Mast cells initiate and maintain inflammation.111 They may play an important part in the development of fibrosis125 and appear to be able to maintain a pro-fibrotic response, producing and storing many of the cytokines that promote fibrosis14,111 (see below under Cytokines), including TNF-, IL-17 and TGF-.125,126 Mast cells numbers are increased in fibrotic organs including the lung,127 heart and kidneys. This suggests that this virus is a significant risk factor for arthrofibrosis, with the risk potentially higher for post-operative patients and those with residual fibrosis. Sanders, T. L. et al. Immunol. One review found that MUAs had caused hemarthroses, wound dehiscence, subdural haematoma, bone fracture and two fatal pulmonary emboli, but reported that most studies did not include enough patients to show up these risk factors.36. Swiss Med. Understanding arthrofibrosis, its causes, rates of occurrence and the success or failure of treatments has been complicated because the condition was poorly defined.32 Definitions have varied widely and are sometimes subjective, as are measures of treatment outcomes.33 Recently, an international panel of experts from multiple medical disciplines developed a consensus definition and classification of knee arthrofibrosis, which stated post-operative fibrosis of the knee was defined as a limited ROM in extension and/or flexion, measured by active flexion and extension, which was not caused by infection of other specific causes.32 Mild, moderate and severe arthrofibrosis was classified as flexion range of 90100, 7089, and less than 70, respectively, and/or a loss of extension of 510, 1120 and more than 20o, respectively.32 The presence of pain was acknowledged as being an important aspect of the condition. Several TGF- neutralising antibodies as well as receptor blocking antibodies have been developed and have passed early clinical trials for fibrotic diseases and cancer.94. Orthop. Qiu, W. et al. The presence of the inflammatory cytokines tumour necrosis factor alpha (TNF-) and interleukin-1 (IL-1) in acute pulmonary fibrotic tissue, but not in older fibrotic tissue,53 suggests one way in which active and residual fibrosis may differ, and an explanation in part for differing pain levels between the two arthrofibrosis groups, but research is lacking. A20 restricts ubiquitination of pro-interleukin-1beta protein complexes and suppresses NLRP3 inflammasome activity. Luo, Y., Xie, X., Luo, D., Wang, Y. 1 Overall, 112,836 knee arthroplasty procedures are performed each year in the UK 2 and 700,000 in the USA 3 at a total annual cost of around $10.2 billion in the USA. Thus, it does not matter whether the back pain is caused by a degenerative intervertebral disc, improperly heal spine fracture, or pinched nerve in the neck. Dietary potassium regulates vascular calcification and arterial stiffness. Over time the focal adhesions become more complex and further tissue contractions occur, together with extensive collagen cross-linking.108, Myofibroblasts are important in wound healing, however, they are not usually found in healthy tissue.103 They are derived from fibroblasts115,116 and a range of other cells107,113 that have differentiated in response to inflammatory cytokines such as TGF-, IL-1 and IL-6. J. Tradit. Invest. J. Orthop. 74, 430438 (2018). The number of participants in CPM trials is particularly important because only a small proportion of patients develop post-operative arthrofibrosis, and it is only in these patients that a significant gain in ROM would be anticipated. Dean, C. S., Chahla, J., Mikula, J. D., Mitchell, J. J. Drug Des. Transforming growth factor-beta in stem cells and tissue homeostasis. Arthrofibrosis after anterior cruciate ligament reconstruction in children and adolescents. Borchers, A. T. & Gershwin, M. E. Complex regional pain syndrome: a comprehensive and critical review. & Leto, T. L. Hepatitis C virus (HCV) proteins induce NADPH oxidase 4 expression in a transforming growth factor beta-dependent manner: a new contributor to HCV-induced oxidative stress. Villegas, M. R. et al. Unraveling the signaling pathways promoting fibrosis in Dupuytrens disease reveals TNF as a therapeutic target. As a common complication following total knee arthroplasty, arthrofibrosis is a significant cause of pain and disability for patients, with up to 25% of patients requiring . 22, 33913407 (2007). Bone marrow-derived MSCs transform into myofibroblasts in rats293 and organ-resident MSC-like cells have been shown by genetic lineage tracing to transform into myofibroblasts and contribute to fibrosis progression in mice.107 Mice with liver fibrosis treated with bone marrow-derived human MSCs showed that some of the donated cells appeared to differentiate into myofibroblasts in the liver.294,295 It is not known how closely these cells resemble the MSC lineages used in in vitro studies. J. Respir. For example, Evans et al.195 demonstrated that the hypermethylation of a COX-2 transcriptional regulator in lung fibrosis resulted in suppressed COX-2 expression and a fibrotic phenotype. Cochrane Database Syst. Lee, S. Y., Kim, S. I. Int. Soluble TNF mediates the transition from pulmonary inflammation to fibrosis. Other cytokines known to have involvement are TNF-, IL-17, IL-1 and the anti-inflammatory IL-10.139 A combination of inflammatory cytokines upregulates expression of TGF- receptors, and inflammation plays an important role in the development of fibrosis.140. A 2019 study cautions against "aggressive" physical therapy, though, because exercise can trigger inflammation and in some cases worsen the problem. Overlapping and divergent actions of structurally distinct histone deacetylase inhibitors in cardiac fibroblasts. Nonetheless, the few studies of MSCs in humans to date have not demonstrated worsening fibrosis.296,297, It is known that MSCs can contribute to the growth of tumours,290 but a recent small phase I clinical trial of MSCs in the treatment of pulmonary fibrosis reported no adverse safety outcomes.292 Different preparations of MSCs differ in their efficacy, perhaps because of variation in their expression of anti-inflammatory genes.298 The age and origin of MSCs may affect the outcome of fibrosis therapy, as MSCs from different lineages express different proteins that affect their therapeutic potential.299 MSCs from the IFP of patients with OA appear to inhibit the production of inflammatory cytokines in vitro.300. 98-B, 14791488 (2016). In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-alpha. 35, 1221 (2014). Sports Med. 510Knockout of the substance P/neurokinin-1 receptor (SP/NK-1R) axis reduces liver fibrosis and biliary damage in the murine model of primary sclerosing cholangitis (PSC). 1, 4752 (2011). Ao, M. et al. You could be eligible for up to $3,345 per month In SSDI Benefits. Pardo, A., Cabrera, S., Maldonado, M. & Selman, M. Role of matrix metalloproteinases in the pathogenesis of idiopathic pulmonary fibrosis. Zhang, X. et al. Trauma Surg. Wkly 144, w13999 (2014). Importantly, SPMs were shown to be anti-fibrotic in organs including the kidney190 and liver.191 PDGF-induced myofibroblast proliferation is inhibited,190 along with the production of inflammatory cytokines, and SPMs may represent an important new treatment for fibrosis.190 Although SPMs have a short half-life in vivo, more stable synthetic analogues have been developed,192 and may become a useful therapy for a range of inflammatory diseases and fibrosis. Wang, Y., van Boxel-Dezaire, A. H. H., Cheon, H., Yang, J. During normal wound healing and resolution of inflammation some myofibroblasts become apoptotic, while others revert to the original cell type, however, the processes by which this occurs are not yet understood.90 In fibrosis epigenetic alterations in myofibroblasts increase the activity of inflammatory and pro-fibrotic genes118 (see below in Epigenetic alterations), and appear to serve as a type of memory of the insult.108 Myofibroblasts that have reverted back to fibroblasts are more likely to become re-activated when exposed to further insult.60,90 This has implications for repeated joint surgeries as fibrosis may resolve naturally and unnoticed, but the presence of reverted fibroblasts that serve as a store of pre-fibrotic cells may leave the patient susceptible to arthrofibrosis after subsequent surgeries, as discussed earlier. Orthop. Orthopedics 24, 901902 (2001). Everyone is affected by bias, and although well-intentioned, surgeons have a vested interest in reporting positive outcomes from their treatments. Serhan, C. N. et al. Studies often do not specify how ROM is evaluated, and changes in ROM are sometimes reported as relative measures.33 Additionally, it is often not reported how severe ROM limitations are before treatment.33 ROM results are often averaged, obscuring any patterns that may exist in treatment outcomes. Cell. Nat. 190, 805811 (2013). Tech. J. Respir. Common symptoms. Med. In vitro and animal studies show that metformin reduces collagen deposition and proliferation of fibroblasts after initiation of fibrosis compared to non-treated controls,159,264,270 with some of these studies also showing reduced levels of -SMA expression. Phase 2a study of safety/efficacy of collagenase (CCH) in patients with adhesive capsulitis. This prevents a normal range of joint motion and usually occurs after knee trauma or surgery. A number of cell types contribute to the initiation and maintenance of chronic inflammation and fibrotic diseases, including macrophages, myofibroblasts and Th2 cells.62 In addition to these factors, protein complexes within the cytoplasm of cells called inflammasomes produce inflammatory cytokines, and which serve as a type of memory of insult (see below). More trials will be necessary to determine if ketotifen can prevent arthrofibrosis, and evidence suggests that it should be administered soon after surgery or injury for the most effective outcome.14, Although TGF- is the primary inducer of fibrosis,16 blocking its production is complicated by the many essential biological roles it plays.94,144 Some studies therefore aim to modify downstream signalling to minimise side-effects. Reconstr. Favejee, M. M., Huisstede, B. M. A. Kayley M. Usher or Jiake Xu. Osteoarthr. Other aspects of diet and nutrition should also be considered. Unfortunately, the effect of previous surgeries on the outcome of surgery or MUA is seldom mentioned in published studies, and is rarely the main focus of a study.6,11 However, Ipach et al. J. Physiol. It is also likely that for patients that develop active arthrofibrosis, more than 1 or 2 weeks of frequent CPM are required to counter the continuing formation of ECM and adhesions. This study was partly supported by a research grant from the National Natural Science Funding of China (81802235), Zhejiang Experimental Animal Science and Technology Project of China (2018C37112), Project of Basic Scientific Research Programme in Wenzhou (Y20180033). Babis, G. C., Trousdale, R. T., Pagnano, M. W. & Morrey, B. F. Poor outcomes of isolated tibial insert exchange and arthrolysis for the management of stiffness following total knee arthroplasty. Am. Mol. Kalson, N. S. et al. Arthrofibrosis means fibrosis of a joint. Current research on pharmacologic and regenerative therapies for osteoarthritis. The options for the patient and the surgeon in this situation are either to accept the reduced range of motion or have it addressed with non- Matrix Biol. J. Korean Med. Med. Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-beta. Margaritopoulos, G. A., Vasarmidi, E. & Antoniou, K. M. Pirfenidone in the treatment of idiopathic pulmonary fibrosis: an evidence-based review of its place in therapy. Blood 101, 22532260 (2003). Platelet-derived growth factor-D promotes fibrogenesis of cardiac fibroblasts. Scand. Arthrofibrosis may be a useful candidate for testing new therapies since it can be identified early after surgery, unlike fibrosis of organs that are typically detected late in the disease process. Thorac. We suggest that what is termed arthrofibrosis may be two different conditions, (1) an active condition in which ECM formation and inflammation are continuous processes driven by positive feedback loops and (2) residual arthrofibrosis, in which the joint has limited ROM due to existing ECM, but the active inflammatory and ECM deposition phases have resolved. Exp. Neutralising antibodies to IL-11 and the deletion of IL-11 receptors inhibited the effects of TGF-, suggesting new therapeutic targets for fibrosis.143 IL-11 is expressed by fibroblasts and other cells.164 It is a member of the IL-6 family of cytokines, and is also implicated in tumour progression.165, TNF- is thought to be important in the pathogenesis of fibrosis.46,116,166,167,168 It is a pleiotropic inflammatory cytokine169 that causes significant upregulation of TGF- production168,170 and receptor expression140 and may stimulate fibroblast growth and collagen type I expression.171 TNF- also causes fibroblast-like differentiation and inflammation,138 and PGE2 expression.172 TNF- and IL-1 upregulate cyclooxygenase 2 (COX-2) synthesis in response to an insult.158 These cytokines also induce the expression of intracellular adhesion molecule-1 (ICAM-1),158 expressed in vascular endothelium, macrophages and lymphocytes, and associated with the development of fibrosis.59 Roberts et al.152 reported that TNF- and IL-1 upregulated MMPs in vitro, potentially providing some anti-fibrotic effects, however, these cytokines also have pro-fibrotic effects. Arthrofibrosis Symptoms. PLoS ONE 7, e43056 (2012). 91, 188200 (2016). Schroer, W. C. et al. Proc. J. 18, 10281040 (2012). PLoS One 12, e0181946 (2017). Horm. Advice given on the forum is in no way a substitute for consulting with a . J. Orthop. PLoS ONE 11, e0168572 (2016). Exp. The process of Arthrofibrosis begins when the injury or the surgery leads to the formation of excessive scar tissue. Injections of halofuginone are also effective in animal models, and could potentially be used post-surgically in the joints of patients at risk of developing arthrofibrosis. Liu, R. M. & Gaston Pravia, K. A. Oxidative stress and glutathione in TGF-beta-mediated fibrogenesis. Many cytokines have been associated with fibrosis, the most important being TGF-. The bones of the knee joint work together, allowing the knee to function smoothly. J. Arthroplast. Mol. Scar tissue is dense and fibrous. Pharmaceuticals 3, 22912321 (2010). & Stark, G. R. STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Marks, P. H. & Donaldson, M. L. Inflammatory cytokine profiles associated with chondral damage in the anterior cruciate ligament-deficient knee. Spira, G. et al. Plast. 23, 11651171 (2005). 14, 477492 (2002). Not doing so is misleading and makes interpretation of results difficult. Arthrofibrosis is characterized by an . Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. Rev. 99, 10781085 (2017). A. et al. Forensic Sci. J. Mol. Immunol. 5, 275289 (2015). 474, 23272336 (2016). Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. Trauma Surg. Aggressive exercise of the affected limb used to be prescribed to those suffering from arthrofibrosis. The complex role of vitamin D in autoimmune diseases. Assess. Boudreau, H. E., Emerson, S. U., Korzeniowska, A., Jendrysik, M. A. J. Orthop. & Choi, M. E. Therapeutic targets for treating fibrotic kidney diseases. 6, 557572 (2010). Zhang, C. et al. Lab. 26, 697704 (2017). Metformin alleviates bleomycin-induced pulmonary fibrosis in rats: pharmacological effects and molecular mechanisms. 31, 3147 (2013). 361, 140150 (2017). In addition, halofuginone inhibits the development of Th17 cells,44 decreasing Th17 cell numbers and inflammatory cytokines via AMP-activated protein kinase-mediated NF-B p65 inactivation.275 Halofuginone has undergone clinical trials to treat Duchenne muscular dystrophy and several forms of cancer using an oral encapsulated form to prevent gastric bleeding. Exp. The process also can cause your muscles and connective tissues to shorten and harden (called contractures.). Preventing arthrofibrosis after surgery is best accomplished with early range of motion rehabilitation. 42, 5167 (2012). Ageing Res. Collagenase nanocapsules: an approach to fibrosis treatment. Proc. Sivakumar, P., Kitson, C. & Jarai, G. Modeling and measuring extracellular matrix alterations in fibrosis: challenges and perspectives for antifibrotic drug discovery. Effect of femoral component design on patellofemoral crepitance and patella clunk syndrome after posterior-stabilized total knee arthroplasty. Shahrara, S. et al. J. van de Laar, I. M. et al. 44, 648655 (2017). which causes significant disability and limitation in . Association of diabetes mellitus with the risk of developing adhesive capsulitis of the shoulder: a longitudinal population-based followup study. Millet, P. J., Johnson, B., Carlson, J., Krishnan, S. & Steadman, J. R. Rehabilitation of the arthrofibrotic knee. These diverse stimuli include ROS, adenosine triphosphate (ATP), mitochondrial DNA and proteins released from damaged ECM, such as hyaluronan, heparin sulphate and biglycan.2,120. 24, 215222 (2016). FASEB J. Stiffness in the joint. 734, 8390 (2014). The fibrotic scar tissue that forms in the joint is known as extracellular matrix (ECM), and is primarily composed of collagen. 300, F898F905 (2011). 31, 811817 (2011). & Kluba, T. Arthrofibrosis after TKAInfluence factors on the absolute flexion and gain in flexion after manipulation under anaesthesia. Patient outcomes after observation versus debridement of unstable chondral lesions during partial meniscectomy: the chondral lesions and meniscus procedures (ChAMP) randomized controlled trial. 293, 17 (2016). & Noble, N. A. Cellular response to hypoxia involves signaling via Smad proteins. Monument et al.262 found that ketotifen treatment reduced arthrofibrosis in rabbits by decreasing the numbers of mast cells and myofibroblasts. Suppl. Alternate-day fasting protects the rat heart against age-induced inflammation and fibrosis by inhibiting oxidative damage and NF-kB activation. Koli, K., Myllarniemi, M., Keski-Oja, J. Halofuginone directly inhibits Smad3 signalling by TGF-.15,114 Smad3 upregulates the production of pro-fibrotic proteins and miRNAs,147 and is considered essential in the fibrotic process.144 Halofuginone reduces collagen type I, suppresses myofibroblast proliferation and has been shown to resolve and reverse established fibrosis in animals models.15,273 The reduction in collagen type I synthesis appears to be the result of inhibited gene expression15,274 and only occurs in soft tissues, not in bone.15. Sterile arthrofibrosis is typically caused by chronic or repetitive injury or surgery that leads to a dysregulated immune reaction and fibrosis in and/or around a joint2 to varying degrees. The inflammatory cytokines and mediators that trigger fibrosis, together with the cells that express them (see below), are essential components of a healthy immune system. & Selman, M. Matrix metalloproteases in aberrant fibrotic tissue remodeling. Arthrofibrosis. The first treatment for arthrofibrosis is rest, ice, and anti-inflammatory medications to reduce the pain and swelling. Respir. Rep. 3, 253261 (2015). 129, 375387 (2018). Oncotarget 8, 101784101794 (2017). Low-dose aspirin can be effective, particularly if taken with omega 3 fatty acids. & Borthwick, L. A. Epigenetic reprogramming in liver fibrosis and cancer. J. Pharmacol. Panni, S. A., Cerciello, S., Vasso, M. & Tartarone, M. Stiffness in total knee arthroplasty. Clin. J. Pathol. 23, 251257 (2004). 10648054 thesis (West Chester University of Pennsylvania, Ann Arbor, USA, 2017). Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels. PubMed Central Koshy, P. J. et al. Surgical lysis and removal of ECM, and MUA, remain the primary treatments for arthrofibrosis. Altern. Biol. Bone Res. Young, S. K., Baird, T. D. & Wek, R. C. Translation regulation of the glutamyl-prolyl-tRNA synthetase gene EPRS through bypass of upstream open reading frames with noncanonical initiation codons. 79, 300310 (2011). Arthrofibrosis of the knee. Evaluation and treatment of disorders of the infrapatellar fat pad. Knee Arthrofibrosis. Zhang, Y., Lee, T. C., Guillemin, B., Yu, M. C. & Rom, W. N. Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure. Theory Pract. Dennis, D. A. Traumatol. In addition, IL-1 receptor antagonists (RA) such as anakinra bind to IL-1 receptors, blocking IL-1 from binding, and have been used successfully to prevent arthrofibrosis in small studies282,283 and fibrosis of organs.98,284 These results suggest that IL-1 is an important player in fibrogenesis, however, further research is needed to investigate the efficacy of anakinra and similar products in preventing or treating arthrofibrosis. Eur. This forms adhesions within joint capsules and contracts tendons and bursa around the joint,3 causing the loss of joint flexion and/or extension. The Orthopaedic Section of the American Physical Therapy Association presents this fifth set of clinical practice guidelines on knee pain and mobility impairments, linked to the International Classification of Functioning, Disability, and Health (ICF). Metformin prevents peritendinous fibrosis by inhibiting transforming growth factor- signaling. The human leucocyte antigen complex is involved in immune system functioning. Ther. Sci. Natl Acad. Hinz, B. et al. Biophys. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. which can restrict joint movement and cause significant pain and disability. However, myofibroblasts also produce TGF-, IL-1, IL-6 and platelet-derived growth factor (PDGF), in addition to reactive oxygen species (ROS) and a range of paracrine signals that further activate a fibrotic response (for reveiw see ref.

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