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.

Keywords: Dpp3; bone mineral density; fragility fracture; osteoporosis; oxidative stress; serum biomarker.

Figure 1

Dpp3 activity in the serum of controls (n = 36) and postmenopausal women with severe osteoporosis (n = 69) at baseline. Statistical significance was calculated using two-tailed Mann–Whitney test; p < 0.001.

Figure 2

(A) Pearson correlation analysis (two-tail) between femoral neck BMD (FN-BMD) and circulating Dpp3 activity in our cohorts of controls (depicted as red circles, n = 36) and patients (depicted as black triangles, n = 67); (B) Pearson correlation analysis (two-tail) between the bone turnover markers CTX (left) and P1NP (right) and circulating Dpp3 activity in our cohort of osteoporotic women at baseline (n = 69).

Figure 3

Pearson correlation analysis (two-tail) between age (left panel) or years from menopause (right panel) and Dpp3 activity in the serum of controls (depicted as red circles, n = 36) and postmenopausal women with severe osteoporosis (depicted as black triangles, n = 69) at baseline.

Figure 4

Serum CTX and P1NP levels (A) and Dpp3 activity (B) in our cohort of postmenopausal women with severe osteoporosis at baseline (T0, black triangles) and 2 weeks after the first dose of the antiresorptive drug denosumab (T1, blue triangles).