OPN-a induces muscle inflammation by increasing recruitment and activation of pro-inflammatory macrophages

While OPN is an important mediator of muscle remodeling in health and disease, functional differences in human spliced OPN variants in the muscle microenvironment have not been characterized. We thus sought to define the pro-inflammatory activities of human OPN isoforms (OPN-a, OPN-b, and OPN-c) on cells present in regenerating muscle. OPN transcripts were quantified in normal and dystrophic human and dog muscle. Human macrophages and myoblasts were stimulated with recombinant human OPN protein isoforms and cytokine mRNA and protein induction was assayed. OPN isoforms were greatly increased in dystrophic human (OPN-a> OPN-b> OPN-c) and dog muscle (OPN-a = OPN-c). In healthy human muscle, mechanical loading also upregulated OPN-a expression (8-fold; P < 0.01), but did not significantly upregulate OPN-c expression (2-fold; P > 0.05). In vitro, OPN-a displayed the most pronounced pro-inflammatory activity among isoforms, acting on both macrophages and myoblasts. In vitro and in vivo data revealed OPN-a upregulated tenascin-c (TNC), a known TLR4 agonist. Inhibition of TLR4 signaling attenuated OPN-mediated macrophage cytokine production. In summary, OPN-a is the most abundant and functionally active human spliced isoform the skeletal muscle microenvironment. Here, OPN-a promotes pro-inflammatory signaling in both macrophages and myoblasts possibly through induction of TNC-TLR4 signaling. Together, our findings suggest that specific targeting of OPN-a and/or TNC signaling in the damaged muscle microenvironment may be of therapeutic relevance.

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