Abstract
Lipocalin 2 (Lcn2) is an adipokine involved in bone and energy metabolism. Its serum levels correlate with bone mechanical unloading and inflammation, two conditions representing hallmarks of Duchenne Muscular Dystrophy (DMD). Therefore, we investigated the role of Lcn2 in bone loss induced by muscle failure in the MDX mouse model of DMD. We found increased Lcn2 serum levels in MDX mice at 1, 3, 6, and 12 months of age. Consistently, Lcn2 mRNA was higher in MDX versus WT muscles. Immunohistochemistry showed Lcn2 expression in mononuclear cells between muscle fibres and in muscle fibres, thus confirming the gene expression results. We then ablated Lcn2 in MDX mice, breeding them with Lcn2−/− mice (MDXxLcn2−/−), resulting in a higher percentage of trabecular volume/total tissue volume compared to MDX mice, likely due to reduced bone resorption. Moreover, MDXxLcn2−/− mice presented with higher grip strength, increased intact muscle fibres, and reduced serum creatine kinase levels compared to MDX. Consistently, blocking Lcn2 by treating 2-month-old MDX mice with an anti-Lcn2 monoclonal antibody (Lcn2Ab) increased trabecular volume, while reducing osteoclast surface/bone surface compared to MDX mice treated with irrelevant IgG. Grip force was also increased, and diaphragm fibrosis was reduced by the Lcn2Ab. These results suggest that Lcn2 could be a possible therapeutic target to treat DMD-induced bone loss.
Highlights
Lipocalin 2 (Lcn2) is a multifunctional protein involved in inflammation [1], acute kidney injury [2], and bone [3,4,5,6] and muscle [7,8,9] pathophysiology
Since Lcn2 is involved in inflammation, to understand its potential role in Duchenne Muscular Dystrophy (DMD) pathophysiology, we first evaluated its concentration in sera of WT and MDX mice, finding that it was significantly higher in the MDX mice at 1, 3, 6, and 12 months of age (Figure 1A)
We show that the genetic ablation of Lcn2 or the inhibition of its function by an Lcn2-blocking antibody in the MDX mouse model of DMD can counteract bone loss
Summary
Lipocalin 2 (Lcn2) is a multifunctional protein involved in inflammation [1], acute kidney injury [2], and bone [3,4,5,6] and muscle [7,8,9] pathophysiology. Lcn emerges as a complex player in bone biology, being detrimental for bone health when upregulated in hindlimb suspension and head-down tilt bed rest in mice and humans, respectively [4], but causing osteopenia in basal conditions when absent [6]. We recently demonstrated that Lcn is increased following acute high-intensity exercise in humans and that it might be detrimental for muscle differentiation. Genetic ablation of Lcn in mice does not negatively affect muscle physiology [9]. Taken together, these findings show that Lcn is a complex molecule, playing different roles in different contexts
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