Gene delivery of TGF-β1 induces arthrofibrosis and chondrometaplasia of synovium in vivo

Abstract

To understand the cellular and molecular events contributing to arthrofibrosis, we used an adenovirus to deliver and overexpress transforming growth factor-beta 1 (TGF-β1) cDNA (Ad.TGF-β1) in the knee joints of immunocompromised rats. Following delivery, animals were killed periodically, and joint tissues were examined macroscopically and histologically. PCR-array was used to assay alterations in expression patterns of extracellular matrix (ECM)-associated genes. By days 5 and 10, TGF-β1 induced an increase in knee diameter and complete encasement of joints in dense scar-like tissue, locking joints at 90° of flexion. Histologically, massive proliferation of synovial fibroblasts was seen, followed by their differentiation into myofibroblasts. The fibrotic tissue displaced the normal architecture of the joint capsule and fused with articular cartilage. RNA expression profiles showed high levels of transcription of numerous MMPs, matricellular and ECM proteins. By day 30, the phenotype of the fibrotic tissue had undergone chondrometaplasia, indicated by cellular morphology, matrix composition and >100-fold increases in expression of collagen type II and cartilage link protein. Pre-labeling of articular cells by injection with recombinant lentivirus containing eGFP cDNA showed fibrotic/cartilaginous tissues appeared to arise almost entirely from local proliferation and differentiation of resident fibroblasts. Altogether, these results indicate that TGF-β1 is a potent inducer of arthrofibrosis, and illustrate the proliferative potential and plasticity of articular fibroblasts. They suggest the mechanisms causing arthrofibrosis share many aspects with tumorigenesis.

Early Response of Mouse Joint Tissue to Noninvasive Knee Injury Suggests Treatment Targets

“…Our study indicated an important role of synovial cells in the process of neocartilage metaplasia that was observed primarily at the transition zone where the synovium connects to the meniscus or articular cartilage, mimicking the osteophyte formation observed in OA. Watson and colleagues (28) observed similar ectopic chondrogenesis and reported that gene delivery of transforming growth factor ␤1 induced massive proliferation of synovial fibroblasts and chondrometaplasia of synovium in vivo (28).…”

Direct bone morphogenetic protein 2 and Indian hedgehog gene transfer for articular cartilage repair using bone marrow coagulates

“…Specifically, the direct gene transfer of TGFB1 to synovial lining cells by intraarticular injection of adenoviral vectors resulted in fibrosis and ectopic chondrogenesis in native and arthritic leporine knee joints 24 , as well as in native knee joints of immunocompromised rats 25 . Using a method of indirect in vivo gene therapy, Gelse et al transplanted perichondrial mesenchymal stromal cells after ex vivo transduction with adenoviral vectors carrying BMP2 genes into chondral defects of rat knees 26 .…”

Complications of Tibial Eminence and Diaphyseal Fractures in Children

“…The exact etiology is unknown, but proposed causes include a genetic predisposition to scar formation, an aberrant inflammatory response to an injury or surgery, or simply prolonged joint immobilization. 12,13 Arthrofibrosis is seen most commonly in children after treatment of tibial eminence fractures. Patel et al 9 retrospectively reviewed 40 patients with tibial eminence fractures and concluded that those who started range-of-motion exercises .4 weeks after injury required more time to return to full activity and were 12 times more likely to develop arthrofibrosis.…”