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The dipeptidyl peptidase 3 (<i>Dpp3</i>) is a ubiquitous zinc-dependent aminopeptidase, participating in the activation or degradation of signaling peptides and in the Keap1–Nrf2 antioxidant pathway. The absence of <i>Dpp3</i> in the <i>Dpp3</i> knockout mouse model causes increased osteoclast activity, altered osteogenic function, sustained oxidative stress in the bone tissue, and bone loss. We aimed to assess the association of <i>Dpp3</i> activity with bone fragility in postmenopausal osteoporosis and the impact of denosumab on enzymatic activity. We conducted a two-phase study including 69 postmenopausal women with severe osteoporosis and 36 postmenopausal women without osteometabolic conditions, as controls (cross-sectional phase). Subjects with severe osteoporosis were assessed at baseline and 14 days after the first denosumab administration (prospective phase). The results showed significant reduction in serum <i>Dpp3</i> activity (expressed as nmoles of formed product/mg proteins/min) in patients vs. controls (0.791 ± 0.232 vs. 1.195 ± 0.338; <i>p</i> < 0.001), and significant association with bone mass at the femoral neck (r = 0.28, <i>p</i> = 0.02) in patients prior to treatment. We found a negative correlation between C-terminal telopeptide (CTX) or N-terminal pro-peptide of type 1 procollagen (P1NP) levels and <i>Dpp3</i> activity (respectively, r = −0.29, <i>p</i> = 0.012; and r = −0.2572, <i>p</i> = 0.033). <i>Dpp3</i> activity did not change after denosumab injection. Our findings support a critical role played by <i>Dpp3</i> in bone homeostasis as a potential bone protective factor. Additional clinical studies in larger cohorts might explore the implementation of <i>Dpp3</i> assessment as a biomarker of bone health status.