DPP3 deficiency impacts bone quality and sensitizes to metabolic alterations

The goal of this study was to evaluate whether the dipeptidyl peptidase 3 (DPP3), recently recognized as a key molecule in bone pathophysiology and proposed as a biomarker of bone health status, plays a role in skeletal and systemic alterations induced by common unbalanced nutritional conditions. We focused on nutrient excess, and in particular on excessive intake of calories from fat, which is known to predispose to osteoporosis, among other complications. Based on the known sex differences in metabolic processes, we considered the impact of this variable, too, in our experimental setting. In detail, we fed young adult male and female C57BL/6J wild-type (WT) and Dpp3 knock-out (Dpp3 ko) mice with 45% kcal fat Western diet for 14 weeks. We assessed DPP3 concentration and enzymatic activity in the serum of WT mice, and performed microstructural (trabecular and cortical), biomechanical (damage resistance and elastic deformation), and histological analysis of bone, and serological analysis of glucose metabolism and inflammatory markers. We found that DPP3 concentration/activity ratio strongly depended on sex and diet (both alone and in combination), and that metabolic response to high fat diet, bone microstructural changes particularly affecting the trabecular compartment and resulting in different biomechanical properties, and changes in bone turnover markers in the peripheral blood were moderately different as a function of the genotype. Of note, DPP3 protein levels in the serum correlated with clinically relevant parameters, including insulin, bone volume/total volume ratio, and serum tartrate-resistant acid phosphatase. This work agrees with a possible role for DPP3 as a biomarker of bone health in relation to diet and justifies studies in the context of other preclinical models of malnutrition, as well as in cohorts of patients.