Abstract
A large number of human diseases are caused by chronic tissue injury with fibrosis potentially leading to organ failure. There is a need for more effective anti-fibrotic therapies. Congenital muscular dystrophy type 1A (MDC1A) is a devastating form of muscular dystrophy caused by laminin α2 chain-deficiency. It is characterized with early inflammation and build-up of fibrotic lesions, both in patients and MDC1A mouse models (e.g. dy3K/dy3K). Despite the enormous impact of inflammation on tissue remodelling in disease, the inflammatory response in MDC1A has been poorly described. Consequently, a comprehensive understanding of secondary mechanisms (impaired regeneration, enhanced fibrosis) leading to deterioration of muscle phenotype in MDC1A is missing. We have monitored inflammatory processes in dy3K/dy3K muscle and created mice deficient in laminin α2 chain and osteopontin or galectin-3, two pro-inflammatory and pro-fibrotic molecules drastically increased in dystrophic muscle. Surprisingly, deletion of osteopontin worsened the phenotype of dy3K/dy3K mice and loss of galectin-3 did not reduce muscle pathology. Our results indicate that osteopontin could even be a beneficial immunomodulator in MDC1A. This knowledge is essential for the design of future therapeutic interventions for muscular dystrophies that aim at targeting inflammation, especially that osteopontin inhibition has been suggested for Duchenne muscular dystrophy therapy.
Highlights
Osteopontin levels in normal skeletal muscle are very low[30,31], pleiotropic roles of the cytokine in injured or diseased muscle have recently become evident
The complexity of osteopontin interactions is illustrated by its multidirectional influence on cells that contribute to muscle repair and/or muscle deterioration: the molecule is associated with intricate regulation of inflammation that prompts myogenic cell proliferation and differentiation as well as fibrogenic cell differentiation[22,32,33,35]
These data suggest that inflammation is the link between myogenesis and fibrosis and osteopontin could be the immunomodulator of muscle diseases
Summary
Osteopontin levels in normal skeletal muscle are very low[30,31], pleiotropic roles of the cytokine in injured or diseased muscle have recently become evident. The deletion of osteopontin in mdx mice resulted in reduced fibrosis and improvement of muscle strength, possibly through skewing the macrophage population towards a pro-regenerative phenotype, demonstrating osteopontin’s powerful properties to control macrophage polarization in the dystrophic muscle[37]. These data suggest that inflammation is the link between myogenesis and fibrosis and osteopontin could be the immunomodulator of muscle diseases. Its impact on disease progress in MDC1A has not been demonstrated, there is a dramatic increase of osteopontin expression in muscle from patients and dyw/dyw mice (animals that express low amounts of truncated laminin α2 chain)[31,38].
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