Multiomics profiling of bone in the Dpp3-deficient mice unveils altered protein and lipid composition

Purpose: Bone is a unique specialized connective tissue comprising inorganic and organic components which continuously undergoes remodeling through the activity of anabolic and catabolic pathways. Peptidases are enzymes cleaving peptide bonds in a broad range of substrates and hence involved in many pathophysiological mechanisms. We previously reported that lack of Dpp3 in the mouse model results in bone loss and here we aimed to establish whether it also affected bone matrix composition. Methods: We performed proteomic and lipidomics analysis of the flushed bone of 6-month-old wild type (WT) and Dpp3 knock-out (ko) male mice (4 mice/genotype); Western blot analysis of selected upregulated proteins and gene expression analysis of genes potentially involved in the identified pathways. Results: We found that Dpp3 deficiency was associated with a proteomic signature in the bone matrix consistent with sustained oxidative stress and altered matrix turnover and pointing to a metabolic adaptation within the skeletal tissue. Accordingly, lack of Dpp3 resulted in a shift in lipid composition in the bone matrix, with enrichment of specific structural lipids and lack of others for energy production. Conclusion: Our work confirms the importance of DPP3 in the context of bone homeostasis and sheds some light on the matrix composition of DPP3-depleted bone. Owing to the foreseen translational implications of this evidence, further investigation is deserved to complete a comprehensive characterization.