Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy

Abstract

In Duchenne muscular dystrophy (DMD) and the mdx mouse model, the absence of the cytoskeletal protein dystrophin causes defective anchoring of myofibres to the basal lamina. The resultant myofibre degeneration and necrosis lead to a progressive loss of muscle mass, increased fibrosis and ultimately fatal weakness. Connective tissue growth factor (CTGF/CCN-2) is critically involved in several chronic fibro-degenerative diseases. In DMD, the role of CTGF might extend well beyond replacement fibrosis secondary to loss of muscle fibres, since its overexpression in skeletal muscle could by itself induce a dystrophic phenotype. Using two independent approaches, we here show that mdx mice with reduced CTGF availability do indeed have less severe muscular dystrophy. Mdx mice with hemizygous CTGF deletion (mdx-Ctgf+/-), and mdx mice treated with a neutralizing anti-CTGF monoclonal antibody (FG-3019), performed better in an exercise endurance test, had better muscle strength in isolated muscles and reduced skeletal muscle impairment, apoptotic damage and fibrosis. Transforming growth factor type-β (TGF-β), pERK1/2 and p38 signalling remained unaffected during CTGF suppression. Moreover, both mdx-Ctgf+/- and FG-3019 treated mdx mice had improved grafting upon intramuscular injection of dystrophin-positive satellite cells. These findings reveal the potential of targeting CTGF to reduce disease progression and to improve cell therapy in DMD.

Increased CCN2, substance P and tissue fibrosis are associated with sensorimotor declines in a rat model of repetitive overuse injury

“…FG-3019 has also been used as a therapy in a mouse model of Duchenne muscular dystrophy, where it reversed muscle fibrosis and even improved motor function (Morales et al 2013). These studies combined with our current and recent (Gao et al 2013) findings of increased CCN2 in tissues and serum support the use of CCN2 as a biomarker of fibrosis in patients with WMSDs.…”

A healthy tension in translational research

“…Furthermore, losartan rescued disease manifestations outside of the cardiovascular system in MFS model mice, including developmental emphysema (7) and skeletal muscle myopathy (8). This work revealed that the congenital myopathy seen in children with severe MFS reflects a TGF-β-induced failure of muscle regeneration and that the protection afforded by TGF-β antagonism extends to mouse models of other myopathic conditions, including Duchenne muscular dystrophy (8), a finding that has been substantiated by others (9)(10)(11)(12)(13)(14)(15). Other groups have subsequently shown the relevance of TGF-β and losartan to animal models of limb-girdle and congenital merosin-deficient muscular dystrophy and to muscle healing in general (16)(17)(18)(19).…”

Transforming growth factor type‐β inhibits Mas receptor expression in fibroblasts but not in myoblasts or differentiated myotubes; Relevance to fibrosis associated to muscular dystrophies

“…Importantly, TGF-b signaling remained unaffected during CTGF suppression [11]. Moreover, blockage of Ang II receptor, AT-1, by losartan diminished skeletal muscle fibrosis, reducing the TGF-b mediated canonical signaling in skeletal muscle fibers [12].These observations indicated that the level of action of these profibrotic factors is specific, either regarding cell type or signaling pathways involved.…”