The Combination of icariin and constrained dynamic loading stimulation attenuates bone loss in ovariectomy‐induced osteoporotic mice

Osteoporosis is a disease characterized by low bone mass and progressive destruction of bone microstructure, resulting in increasing the risk of fracture. Icariin (ICA) as a phytoestrogen shows osteogenic effects, and the mechanical stimulation has been demonstrated the improving effect on osteoporosis. The objective of this study was to investigate the effect of ICA in combination with constrained dynamic loading (CDL) stimulation on osteoporosis in ovariectomized (OVX) mice. The serum hormone levels, bone turnover markers, trabecular architecture, ulnar biomechanical properties, and the expression of osteoblast‐related gene (alkaline phosphatase, ALP; osteocalcin, OCN; bone morphogenetic protein‐2, BMP‐2; Collagen I (α1), COL1; osteoprotegerin, OPG) and osteoclast‐related genes (receptor activators of NF‐κB ligand, RANKL; tartrate‐resistant acid phosphatase, TRAP) were analyzed. The results showed that ICA + CDL treatment could increase the osteocalcin (20.85%), estradiol levels (20.61%) and decrease the TRAP activity (26.27%) significantly than CDL treatment. The combined treatment attenuated bone loss and biomechanical decrease more than single use of CDL treatment. ICA + CDL treatment significantly up‐regulated the level of osteoblast‐related gene expression and down‐regulated the osteoclast‐related genes expression; moreover, the combined treatment increased the ratio of OPG/RANKL significantly compared to ICA (72.83%) or CDL (65.63%) treatment alone. The present study demonstrates that icariin in combination with constrained dynamic loading treatment may have a therapeutic advantage over constrained dynamic loading treatment alone for the treatment of osteoporosis, which would provide new evidence for the clinical treatment of osteoporosis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1415–1424, 2018.

     

Pharmacological inhibition of heparin-binding EGF-like growth factor promotes peritoneal angiogenesis in a peritoneal dialysis rat model

Background

Molecular mechanisms of peritoneal dialysis (PD) ultrafiltration failure, peritoneal neo-angiogenesis, and fibrosis remain to be determined. We aimed to determine the role of heparin-binding EGF-like growth factor (HB-EGF) inhibition on angiogenesis of peritoneal membrane in a PD rat model.

Methods

32 male Wistar rats were assigned into (1) control group; (2) uremic non-PD group: subtotal nephrectomy-induced uremic rats without PD; (3) uremic rats subjected to PD: uremic rats that were dialyzed with Dianeal^® for 4 weeks; (4) CRM 197 group: dialyzed uremic rats were supplemented with CRM197, a specific HB-EGF inhibitor. Peritoneal transport function was examined by peritoneal equilibration test. Expression of HB-EGF and EGFR in peritoneal samples were examined by real-time PCR, immunohistochemical staining, and western blot.

Results

Progressive angiogenesis and fibrosis were observed in uremic PD rats, and there were associated with decreased net ultrafiltration (nUF), increased permeability of peritoneal membrane, and reduced expression of HB-EGF and EGFR protein and mRNA in uremic PD rats compared to uremic non-PD or control groups (both p < 0.05). CRM197 significantly induced peritoneal membrane permeability, decreased nUF, increased higher vessel density, and reduced pericyte count compared to that of uremic PD rats. The levels of HB-EGF and EGFR expression negatively correlated with vessel density in peritoneal membrane (both p < 0.001).

Conclusion

PD therapy was associated with peritoneal angiogenesis, functional deterioration, and downregulation of HB-EGF/EGFR. Pharmacological inhibition of HB-EGF promoted PD-induced peritoneal angiogenesis and fibrosis and ultrafiltration decline, suggesting that HB-EGF downregulation contributes to peritoneal functional deterioration in the uremic PD rat model.