Bone Abstracts

Previous studies demonstrated a negative influence of the growth- and differentiation factor midkine (MDK) on bone formation during bone remodeling and fracture healing. Additionally, MDK-deficiency protected mice from a loss of trabecular bone mass after ovariectomy (OVX). Therefore, we hypothesized that MDK may also be involved in the pathogenesis of delayed, osteoporotic fracture healing after OVX in mice. Thus, we analyzed the expression of MDK during bone regeneration and the effects of MDK-antibody (MDK-Ab) therapy on both bone healing and the intact skeleton in OVX-mice.

12-weeks-old, female C57BL/6J mice were either sham-operated or ovariectomized. 8 weeks later, all animals received a femur osteotomy and were treated with vehicle or MDK-Ab twice per week for three weeks. The mice were sacrificed at day 3, 10 or 23 and the fractured and intact femurs were assessed by 3-point-bending-test, μCT or immunohistochemical analysis. MDK serum levels were determined by ELISA.

Interestingly, OVX-mice displayed significantly increased MDK serum levels at day 10 (62 pg/ml) in comparison to control-mice (<5 pg/ml) and showed significantly delayed fracture healing. Treatment with MDK-Ab abolished the increase in MDK serum level and led to a significantly increased relative flexural rigidity (+92%) and bone volume fraction (+38%) in the callus of OVX-mice at day 23. Immunohistochemical staining demonstrated a significantly higher expression of beta-catenin in the fracture callus of treated OVX-mice (+122%). Additionally, MDK-Ab treatment led to a significantly increased trabecular bone volume (+58%) and trabecular thickness (+10%) in the intact femurs of OVX-mice.

We conclude that circulating MDK is involved in the pathophysiology of delayed fracture healing after OVX. Antagonizing MDK increased the beta-catenin signaling, leading to a faster callus mineralization and therefore to an accelerated bone repair. This indicates a therapeutic potential for the MDK-Ab to enhance fracture healing in patients with delayed regeneration due to postmenopausal osteoporosis.