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

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.

α2-Antiplasmin is involved in bone loss induced by ovariectomy in mice

“…Further, we have also demonstrated that the fibrinolytic system is crucial to regulate bone metabolism and repair [9,10,[12][13][14]. In contrast, our current results show that plasmin does not affect expression of IL-1β and TNF-α mRNA in monocytic cells, suggesting that stimulation of these cytokines does not require the fibrinolytic system.…”

“…Daci et al revealed that PAI-1 deficiency blunts trabecular bone loss induced by OVX in mice [11]. Our recent study revealed that PAI-1 is involved in diabetic bone loss and delayed bone repair as well as glucocorticoidinduced osteopenia and muscle wasting [12][13][14]. Taken together, the data imply that activation of the fibrinolytic system might regulate bone metabolism in postmenopausal and secondary osteoporosis.…”

“…On the other hand, Daci et al showed that bone remodeling and trabecular bone loss due to estrogen deficiency are suppressed in mice without PAI-1 [11]. PAI-1 is also associated with diabetic bone loss and delayed bone repair as well as glucocorticoid-induced osteopenia in mice [12][13][14]. These findings suggest that regulation of the tissue fibrinolytic system is closely linked to physiological and pathological processes in the bone.…”

Overnutrition, mTOR signaling, and cardiovascular diseases

“…Also, plasma levels of plasminogen activator inhibitor 1 (PAI-1), an inhibitor of fibrinolysis, are generally increased in obese patients and in those with Type 2 diabetes (49). Increased amounts of PAI-1 contribute to reduced plasmin activation and a prothrombotic state, which may promote atherogenesis and increase the risk of CVD (49,72). Conversely, a reduction in plasmin activation is also associated with reduced activation of transforming growth factor-␤ (TGF-␤), a molecule important for suppressing the proliferation and migration of smooth muscle cells that contributes to atherosclerotic lesion formation (71).…”

Stromal cell-derived factor-1 mediates changes of bone marrow stem cells during the bone repair process

“…Recently, we investigated the roles of tissue-fibrinolytic systems and the diabetic state on bone healing using the efficient bone repair model after femoral bone damage in mice (16,17,25). Therefore, in the present study, we examined the effects of bone defect on HSCs and MSCs in bone marrow from the damaged femur in mice and tried to clarify their detailed mechanisms using this model.…”