Plasminogen Activator Inhibitor-1 Is Involved in Impaired Bone Repair Associated with Diabetes in Female Mice

Li Mao,Katsumi Okumoto,Kiyotaka Okada,Naoyuki Kawao,Osamu Matsuo,Yukinori Tamura,Hiroshi Kaji,Masato Yano,Luc Malaval

doi:10.1371/journal.pone.0092686

Abstract

Previous studies suggest that fracture healing is impaired in diabetes; however, the underlying mechanism remains unclear. Here, we investigated the roles of plasminogen activator inhibitor-1 (PAI-1) in the impaired bone repair process by using streptozotocin (STZ)-induced diabetic female wild-type (PAI-1 +/+) and PAI-1-deficient (PAI-1 −/−) mice. Bone repair and the number of alkaline phosphatase (ALP)-positive cells at the site of a femoral bone damage were comparable in PAI-1 +/+ and PAI-1 −/− mice without STZ treatment. Although the bone repair process was delayed by STZ treatment in PAI-1 +/+ mice, this delayed bone repair was blunted in PAI-1 −/− mice. The reduction in the number of ALP-positive cells at the site of bone damage induced by STZ treatment was attenuated in PAI-1 −/− mice compared to PAI-1 +/+ mice. On the other hand, PAI-1 deficiency increased the levels of ALP and type I collagen mRNA in female mice with or without STZ treatment, and the levels of Osterix and osteocalcin mRNA, suppressed by diabetic state in PAI-1 +/+ mice, were partially protected in PAI-1 −/− mice. PAI-1 deficiency did not affect formation of the cartilage matrix and the levels of types II and X collagen and aggrecan mRNA suppressed by STZ treatment, although PAI-1 deficiency increased the expression of chondrogenic markers in mice without STZ treatment. The present study indicates that PAI-1 is involved in the impaired bone repair process induced by the diabetic state in part through a decrease in the number of ALP-positive cells.

Highlights

The risk of fracture is increased in diabetic patients mainly due to impairment of the bone formation process [1,2]
More recent studies have shown that the impaired fracture healing observed in diabetic state might be due to the loss of cartilage caused by increased apoptosis and osteoclastogenesis, which is followed by a reduction in the cartilaginous template for endochondral bone formation [13,14,15]
These findings imply that the tissue fibrinolytic system is involved in the bone repair process

Summary

Introduction

The risk of fracture is increased in diabetic patients mainly due to impairment of the bone formation process [1,2]. More recent studies have shown that the impaired fracture healing observed in diabetic state might be due to the loss of cartilage caused by increased apoptosis and osteoclastogenesis, which is followed by a reduction in the cartilaginous template for endochondral bone formation [13,14,15]. We examined the effects of PAI-1 deficiency on the impaired bone repair in diabetes by using a mouse model of diabetes induced by streptozotocin (STZ) in female wild-type (PAI-1+/+) and PAI-1- deficient (PAI-12/2) mice. Diabetic mouse model Diabetes was induced in female PAI-1+/+ and PAI-12/2 mice by daily intraperitoneal injections of STZ (50 mg/kg body weight, in saline) (Sigma, St Louis, MO, USA, # S0130), a pancreatic b-cell cytotoxin, for 4 days, as previously described [20]. At 2 weeks after induction of diabetes, a bone defect surgery was performed in the right femur of the mice. All statistical analyses were performed using StatView version 5.0 software (SAS Institute; Cary, NC, USA)

Results

Bone repair after a femoral bone defect

Histological analysis of the damaged site after a femoral bone defect

Discussion

Author Contributions