Connective tissue growth factor (CTGF/CCN2) in haemophilic arthropathy and arthrofibrosis: a histological analysis

Abstract

Introduction Joint haemorrhage is the principal clinical manifestation of haemophilia frequently leading to advanced arthropathy and arthrofibrosis, resulting in severe disability. The degree and prevalence of arthrofibrosis in hemophilic arthropathy is more severe than in other forms of arthropathy. Expression of connective tissue growth factor (CTGF) has been linked to many fibrotic diseases, but has not been studied in the context of haemophilic arthropathy. Aim We aim to compare synovial tissues histologically from haemophilia and osteoarthritis patients with advanced arthropathy in order to compare expression of proteins that are possibly aetiologic in the development of arthrofibrosis. Methods Human synovial tissues were obtained from 10 haemophilia and 10 osteoarthritis patients undergoing joint surgery and processed for histology and immunohistochemistry. Results All samples from haemophilia patients had synovitis with hypertrophy and hyperplasia of synovial villi. Histologically, synovial tissues contained hyperplastic villi with increased cellularity and abundant haemosiderin-and ferritin-pigmented macrophage-like cells (HMCs), with a perivascular localization in the sub-surface layer. CTGF staining was observed in the surface layer and sub-surface layer in all haemophilia patients, exclusively co-localizing with HMCs. Quantification showed that the extent of CTGF-positive areas was correlated with the degree of detection of HMCs. CTGF was not observed in any of the samples from osteoarthritis patients. Conclusion Using histological analysis, we showed that CTGF expression is elevated in haemophilia patients with arthrofibrosis and absent in patients with osteoarthritis. Additionally, we found that CTGF is always associated with haemosiderin-pigmented macrophage-like cells, which suggests that CTGF is produced by synovial A cells following the uptake of blood breakdown products.

Total ankle replacement in patients with haemophilic arthropathy: primary arthroplasty and conversion of painful ankle arthrodesis to arthroplasty

“…Arthrofibrosis as a postoperative complication was described in several clinical studies . It has been demonstrated that in haemophilic patients with arthrofibrosis the human synovial tissues expressed elevated levels of connective tissue growth factor which may explain the high prevalence of this complication . To avoid this complication, we recommend intensive preoperative and postoperative physical therapy .…”

Hemophilic arthropathy: Current knowledge and future perspectives

“… 10 , 44 In line with this, synovial membrane specimens from patients with early‐stage hemophilic arthropathy are characterized by inflammation, an increased number of synovial villi, and iron accumulation in macrophages that is greater than that observed in RA patients. 46 , 47 …”

“… 54 , 65 Before the introduction of biological disease‐modifying antirheumatic drugs (DMARDs), RA also frequently progressed to OA, 44 although the degree of synovial fibrotic changes in the context of hemophilic arthropathy is greater than that observed in OA, thus indicating a disease‐specific expression of pro‐fibrotic factors such as connective tissue growth factor. 46 …”

The pathogenic role of connective tissue growth factor in osteoarthritis

“…CTGF plays an important role in many physiological and pathological activities including inflammation, wound-healing, fibrosis, angiogenesis, and carcinogenesis [11,27]. CTGF has been implicated in all fibrotic conditions and detected in joint capsule tissue or contracted joints of the synovium in hemophilia patients [1]. Some evidences identified that increased expression of CTGF could also be involved in the onset of rheumatoid arthritis by enhancing the activity of osteoclasts [9].…”

“…Connective tissue growth factor (CTGF; also known as CCN2) is a member of the CCN (CYR61-CTGF-NOV) family, which is a group of secreted multifunctional proteins [1–3]. CTGF is known to be up-regulated in pathological conditions in regions of severe injury including fibrotic disorders, various cancers, and arthritis.…”