Mice lacking the plasminogen activator inhibitor 1 are protected from trabecular bone loss induced by estrogen deficiency

Bone turnover requires the interaction of several proteases during the reso rption phase. Indirect evidence suggests that the plasminogen activator/pla smin pathway is involved in bone resorption and turnover, and recently we h ave shown that this cascade plays a role in the degradation of nonmineraliz ed bone matrix in vitro. To elucidate the role of the plasminogen activator inhibitor 1 (PAI-1) in bone turnover in vivo, bone metabolism was analyzed in mice deficient in the expression of PAI-1 gene (PAI-1(-/-)) at baseline (8-week-old mice) and 4 weeks after ovariectomy (OVX) or sham operation (S ham) and compared with wild-type (WT) mice. PAI-1 inactivation was without any effect on bone metabolism at baseline or in Sham mice. However, signifi cant differences were observed in the response of WT and PAI-1(-/-) mice to ovariectomy. The OVX WT mice showed, as expected, decreased trabecular bon e volume (BV/TV) and increased osteoid surface (OS/BS) and bone formation r ate (BFR), as assessed by histomorphometric analysis of the proximal tibial metaphysis. In contrast, no significant change in any of the histomorphome tric variables studied was detected in PAI-1(-/-) mice after ovariectomy. A s a result, the OVX PAI-1(-/-) had a significantly higher BV/TV, lower OS/B S, lower mineral apposition rate (MAR) and BFR when compared with the OVX W T mice. However, a comparable decrease in the cortical thickness was observ ed in OVX PAI-1(-/-) and WT mice. In addition, the cortical mineral content and density assessed in the distal femoral metaphysis by peripheral quanti tative computed tomography (pQCT), decreased significantly after ovariectom y, without difference between PAI-1(-/-) mice and WT mice. In conclusion, b asal bone turnover and bone mass are only minimally affected by PAI-1 inact ivation. In conditions of estrogen deficiency, PAI-1 inactivation protects against trabecular bone loss but does not affect cortical bone loss, sugges ting a site-specific role for PAI-1 in bone turnover.