Human xylosyltransferases – mediators of arthrofibrosis? New pathomechanistic insights into arthrofibrotic remodeling after knee replacement therapy

Abstract

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.

Expression of xylosyltransferases I and II and their role in the pathogenesis of arthrofibrosis

“…Dissemination of pro-and anti-inflammatory mediators from thrombocytes, damaged tissue, and recruited, infiltrating cells from the immune system leads to activation and differentiation of fibroblasts. Myofibroblasts are created [15,25]-an intermediate form of connective-tissue cells and smooth muscle cells with the ability to contract and are capable of storing the extracellular matrix: ECM-proteins like collagen and fibronectin are capable of synthesizing XT [10]. The apoptosis of myofibroblasts occurs at the end of the physiological healing process.…”

“…It induces the synthesis of collagens, proteoglycans, and other ECM molecules in the target cells. TGF-β1 can also induce the production of XT-I in fibroblasts [10,17]. XT-I and XT-II catalyze the posttranslational xylosylization of proteoglycan core proteins in the Golgi complex [34].…”

“…Characteristic of AF is fibrotic thickening of the joint capsule that when most severe can cause the total loss of joint mobility [5][6][7]. Its incidence is reported to lie between 4 and 35% after tendon surgery and endoprostheses in the knee joint [8][9][10][11]. Two clinical etiological forms of AF are known: primary and generalized or secondary and localized.…”

“…Wound healing is physiologically controlled by the apoptosis of myofibroblasts. If such apoptosis fails to occur, extracellular substances continue to be secreted, followed by a pathological buildup of scar tissue through tissue contraction and an eventual loss of mobility [10,15]. The inflammatory cytokines and mediators that trigger fibrosis are essential components of a healthy immune system.…”

“…A rise in xylosyltransferase I (XT-I) activity furthers the accumulation of proteoglycan characteristic of fibrotic diseases [17,18]. A trial that enrolled 95 patients with AF and 132 controls, after total knee arthroplasty (TKA), reported no significant XT-I activity in serum [10]. However, patients with other systemic fibrotic diseases like systemic sclerodermia or liver fibrosis did demonstrate elevated serum-XT activity compared to a control cohort [17,19].…”