Dipeptidyl Peptidase 3 Activity as a Promising Biomarker of Bone Fragility in Postmenopausal Women

Abstract

The dipeptidyl peptidase 3 (Dpp3) 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 Dpp3 in the Dpp3 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 Dpp3 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 Dpp3 activity (expressed as nmoles of formed product/mg proteins/min) in patients vs. controls (0.791 ± 0.232 vs. 1.195 ± 0.338; p < 0.001), and significant association with bone mass at the femoral neck (r = 0.28, p = 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 Dpp3 activity (respectively, r = −0.29, p = 0.012; and r = −0.2572, p = 0.033). Dpp3 activity did not change after denosumab injection. Our findings support a critical role played by Dpp3 in bone homeostasis as a potential bone protective factor. Additional clinical studies in larger cohorts might explore the implementation of Dpp3 assessment as a biomarker of bone health status.

Label-free multimodal nonlinear optical microscopy reveals features of bone composition in pathophysiological conditions

“…In conclusion, a non-conventional analysis of bone uncovered a possible metabolic alteration in this tissue in the absence of Dpp3. A recent clinical study proposed DPP3 as a bone protective factor, by showing significant association with femoral neck bone mineral density in post-menopausal osteoporotic women before treatment and significant reduction in patients compared to controls ( Menale et al, 2022 ). Taken together, these findings will deserve further investigation, also considering their possible translational relevance for human bone pathophysiology.…”

DPP3: From biomarker to therapeutic target of cardiovascular diseases

“…A recent clinical trial also found a close relationship between progressive cell death and the high level of DPP3 in plasma during the shock of various etiologies ( 72 ). It is precisely the wide distribution of DPP3 inside and outside cells that make it participating in various physiological and pathological processes, such as oxidative stress ( 73 – 75 ), RAS over-activation ( 45 , 76 ), and inflammation ( 77 , 78 ). Therefore, the above evidence fully indicates that DPP3 is widely distributed in multiple organisms and tissues and may have a broader range of biological functions.…”