Objectives: Xylosyltransferase-I (XT-I) is the downstream key mediator of proteoglycan biosynthesis and fibroblast-to-myofibroblast transition. Previous mechanistic studies demonstrated enhanced XT-I responses in arthrofibrotic synovial fibroblasts; the clinical utility of soluble XT-I and XT-II activity as a biomarker in synovial fluid and serum remains uncertain. Material and Methods: This study used prospectively collected paired synovial fluid and serum samples from a predefined multicenter observational study. The final analytical cohort comprised 39 patients with knee arthrofibrosis and 36 controls with osteoarthritis, loosening of knee prosthesis, and cruciate ligament reconstruction. Selective XT-I and XT-II activities were measured using a ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) activity assay. Between-group comparisons used two-sided Mann-Whitney U tests with rank-biserial effect sizes. Paired synovial-serum comparisons within the arthrofibrosis group and control group used Wilcoxon signed-rank tests. Spearman correlations and receiver operating characteristic (ROC) analyses were performed. One control serum XT-I value was missing and was handled by available-case analysis. Results: Synovial XT-I (median [interquartile range (IQR], 7.43 [4.16-10.73] vs 9.59 [7.41-12.62] mU/L; p = 0.033), serum XT-I (4.24 [3.84-4.72] vs 4.83 [3.80-5.66] mU/L; p = 0.023), and synovial XT-II (3.27 [2.32-4.26] vs 4.19 [3.48-4.82] mU/L; p = 0.018) were lower in the arthrofibrosis group than in controls. Serum XT-II and between-group synovial-to-serum ratios did not differ significantly. Paired synovial fluid-serum analyses showed a consistent isoenzyme-dependent compartmental pattern in both groups: XT-I activity was higher in synovial fluid than in serum, with median synovial-to-serum ratios of 1.82 in arthrofibrosis and 2.13 in controls, whereas XT-II activity was lower in synovial fluid than in serum, with corresponding ratios of 0.55 and 0.73. Synovial and serum values were not significantly correlated. Individual biomarkers showed modest discrimination, with areas under the receiver operating characteristic curve (AUCs) ranging from 0.584 to 0.659. Conclusion: XT activity patterns in knee arthrofibrosis appear to depend on disease stage, biological compartment, and isoenzyme subtype. XT-I showed relative enrichment in synovial fluid, whereas XT-II predominated in serum. The modest diagnostic accuracy argues against the use of a single XT measurement as a stand-alone test but supports further evaluation of XT within time-resolved, multimarker approaches or cellular arthrofibrotic remodeling.

Arthrofibrosis following total knee arthroplasty is a fibroproliferative joint disorder marked by dysregulated biosynthesis of extracellular matrix proteins, such as collagens and proteoglycans. The underlying cellular events remain incompletely understood. Myofibroblasts are highly contractile matrix-producing cells characterized by increased alpha-smooth muscle actin expression and xylosyltransferase-I (XT-I) secretion. Human XT-I has been identified as a key mediator of arthrofibrotic remodeling. Primary fibroblasts from patients with arthrofibrosis provide a useful in vitro model to identify and characterize disease regulators and potential therapeutic targets. This study aims at characterizing primary synovial fibroblasts from arthrofibrotic tissues (AFib) regarding their molecular and cellular phenotype by utilizing myofibroblast cell culture models. Compared to synovial control fibroblasts (CF), AFib are marked by enhanced cell contractility and a higher XT secretion rate, demonstrating an increased fibroblast-to-myofibroblast transition rate during arthrofibrosis. Histochemical assays and quantitative gene expression analysis confirmed higher collagen and proteoglycan expression and accumulation in AFib compared to CF. Furthermore, fibrosis-based gene expression profiling identified novel modifier genes in the context of arthrofibrosis remodeling. In summary, this study revealed a unique profibrotic phenotype in AFib that resembles some traits of other fibroproliferative diseases and can be used for the future development of therapeutic interventions.

Arthrofibrosis (AF) is one of the most frequent complications of injuries and surgical interventions on joints, particularly after total knee replacement and anterior cruciate ligament reconstruction. Even though all joints can be affected, most cases involve the knee joint. Patients feel a painful impairment of the range of motion caused by fibrotic tissue formation within and sometimes also outside the joint. The normal healing process is disturbed by mechanical and emotional stressors and severe pain. In 90% of the cases AF occurs even within the first few days after the injury or surgery, so that the quality standards cannot be achieved. Physiotherapy and rehabilitation often do not result in a substantial amelioration of symptoms, so that the activities of daily living (ADL) are severely limited. The clinical diagnostics, differential diagnostics and a novel pathogenesis and stage model of the primary AF with the treatment principles derived from this are presented in this article.

ZusammenfassungDie Arthrofibrose (AF) gehört zu den häufigsten Komplikationen nach Verletzungen und operativen Eingriffen an Gelenken, v. a. nach Gelenk- und Kreuzbandersatz. Alle großen Gelenke können betroffen sein, am häufigsten ist es jedoch das Kniegelenk. Es kommt zur schmerzhaften Bewegungseinschränkung durch Vermehrung von fibrotischem Gewebe innerhalb und teilweise auch außerhalb des Gelenks. Der normale Heilungsprozess ist durch mechanische und emotionale Stressoren sowie starke Schmerzreize gestört. Die AF tritt zu 90 % schon wenige Tage nach der Verletzung oder Operation auf, sodass die Qualitätsstandards nicht erreicht werden können. Durch Physiotherapie und Rehabilitation kann oft keine wesentliche Verbesserung der Funktion erreicht werden, sodass die Aktivitäten des täglichen Lebens (ADL) stark eingeschränkt sind. Klinische Diagnostik, Differenzialdiagnostik sowie ein neues Pathogenese- und Stadienmodell der primären AF mit den daraus abgeleiteten therapeutischen Prinzipien werden vorgestellt.

Arthrofibrosis of the knee joint is a severe complication following trauma and surgical procedures, which often results in long-term impairment of joint function. Early mobilization techniques and anesthesia are still employed without sufficient clarification of the underlying processes. While the early stages of arthrofibrosis can be successfully treated with conservative measures for pain reduction and wound healing, in the late stage tense collagenous scar tissue is frequently present that permanently limits joint mobility. In this stage an improvement of joint mobility has no chance of success without a surgical intervention. In surgical treatment a differentiation should be made between localized (mostly secondary) arthrofibrosis (e.g. cruciate ligament surgery) and generalized arthrofibrosis (in the majority of cases primarily after total knee arthroplasty) and the treatment planned accordingly. Comorbid pathological alterations (transplant position, instability of the total knee endoprosthesis, implant attrition, low-grade infection, patellofemoral instability or maltracking, patella baja) must be taken into consideration in the treatment. A multimodal accompanying treatment including physiotherapy, pain therapy and psychosomatics is necessary to ensure successful treatment.

Operative Eingriffe für einen Gelenk- oder Kreuzbandersatz sind heute Routine. Dennoch entwickeln manche Patienten im Nachhinein eine Arthrofibrose. Sind die konservativen Maßnahmen ausgeschöpft, kann ein erneuter operativer Eingriff helfen.

Die Knieendoprothetik zählt zu den erfolgreichsten Operationsverfahren in der Medizin und ist für jede orthopädisch-unfallchirurgische Abteilung auch von hoher ökonomischer Bedeutung. Jeder Operateur hat ein sehr großes Interesse daran, dem Patienten durch den Eingriff ein optimal funktionierendes Knie zur Verfügung zu stellen.

Noch immer gilt die Arthrofibrose – die häufigste Komplikation nach Knie-TEP- oder Kreuzband-OP – als Verklebung. Neue Modelle zeigen jedoch, dass Fibroblasten mechanisch sensibel sind, und Behandlungen gegen eine Verklebung wie Dehnungen und Bewegen über die Schmerzschwelle hinaus absolut kontraproduktiv sind. Ein Update der Arthrofibrose-Spezialisten Dr. Phillip Traut und Uwe Rückert.

Die Arthrofibrose nach der Implantation einer Knie-Totalendoprothese gehört mit 1–13 % zu den häufigsten Komplikationen nach diesem Eingriff und ist somit für die relativ hohe Unzufriedenheitsrate der mit einer Knie-Endoprothese versorgten Patienten mitverantwortlich. Da bisher keine Differenzierung zwischen Arthrofibrose und Adhäsion („Verklebung“) vorgenommen wird, werden beide Pathologien nach dem „Verklebungsmodell“ mechanisch behandelt. Bei der Arthrofibrose führt dies meist zu einem schlechten Ergebnis. Das hier vorgestellte zelluläre, Zytokin-basierte Pathogenese- und hypothetische Stadienmodell der Arthrofibrose könnte die bisherige Behandlung dieser schwerwiegenden Komplikation verändern.

Aims and Objectives: Arthrofibrosis is defined as painful impairment of joint flexibility due to fibrotic tissue remodeling after joint trauma or surgery. The incidence of arthrofibrosis after knee replacement surgery is 5 to 10%. Although conventional therapeutic approaches as for instance mobilization and physiotherapy are applied, an effective and causative therapeutic regimen is not known. Materials and Methods: To characterize arthrofibrotic remodeling of the extracellular matrix, to develop new therapeutic approaches and to define diagnostic biomarkers and therapeutic targets, understanding of biochemical principles is urgently required. Fibrotic remodeling was described in several tissues, whereas synovial fibrosis is one of the least investigated fibrotic disorders. Nevertheless, molecular key events in fibrosis seem to be the same and are initiated by exogenic or endogenic tissue damage and differentiation of resident fibroblasts of the connective tissue to myofibroblasts. Known inductors of myofibroblast differentiation are fibrotic growth factors, which are secreted by platelets, damaged tissue and inflammatory cells, as well as mechanical strain. Research studies concerning cardiac fibrosis in tako-tsubo cardiomyopathy also define emotional stress and sympathicotonic destabilization as profibrotic stressors. Myofibroblasts generate contractile forces and synthesize extracellular matrix components, so that scar tissue accumulates. While myofibroblasts disappear by apoptosis in physiological wound healing, they persist in fibrosis. Results: Recently, we could demonstrate that increased expression of human xylosyltransferase (XT)-I, an enzyme which catalyzes the rate limiting step in proteoglycan glycosylation, is linked to abnormal extracellular matrix remodeling. Serum XT activity reflects proteoglycan synthesis rate and is known as fibrosis biomarker in liver fibrosis or scleroderma. Our data also indicate that XT-I is a cellular key mediator of arthrofibrosis. However, we suggest that molecular changes based on arthrofibrosis are, due to local restriction of the affected joint by the blood-synovial-barrier, not detectable in human serum. Currently, we study synovial XT activity of arthrofibrosis patients and controls in a multicenter study. Conclusion: In summary, we give insights into the complex pathobiochemistry of arthrofibrosis as well as current research projects. A deeper characterization of the involved mechanisms might not only contribute to control and inhibit fibrotic remodeling by interfering with components of fibrotic signal cascades but also to establish new therapeutic strategies.

Total knee replacement (TKR) is a common therapeutic option to restore joint functionality in chronic inflammatory joint diseases. Subsequent arthrofibrotic remodeling occurs in 10%, but the underlying pathomechanisms remain unclear. We evaluated the association of xylosyltransferases (XT), fibrotic mediators catalyzing glycosaminoglycan biosynthesis, leading to arthrofibrosis as well as the feasibility of using serum XT activity as a diagnostic marker. For this purpose, synovial fibroblasts (SF) were isolated from arthrofibrotic and control synovial biopsies. Basal α-smooth muscle actin expression revealed a high fibroblast-myofibroblast transition rate in arthrofibrotic fibroblasts. Fibrotic remodeling marked by enhanced XT activity, α-SMA protein expression as well as xylosyltransferase-I, collagen type III-alpha-1 and ACTA2 mRNA expression was stronger in arthrofibrotic than in control fibroblasts treated with transforming growth factor-β1 (TGF-β1). Otherwise, no differences between serum levels of XT-I activity or common fibrosis markers (galectin-3 and growth differentiation factor-15 levels (GDF-15)) were found between 95 patients with arthrofibrosis and 132 controls after TKR. In summary, XT-I was initially investigated as a key cellular mediator of arthrofibrosis and a target for therapeutic intervention. However, the blood-synovial-barrier makes arthrofibrotic molecular changes undetectable in serum. Future studies on monitoring or preventing arthrofibrotic remodeling should therefore rely on local instead of systemic parameters.