Stromelysin (MMP-3) synthesis is up-regulated in estrogen-deficient mouse osteoblasts in vivo and in vitro

Sex steroids are important regulators of bone cell function and osteoblast- derived matrix metalloproteinases (MMPs) are key mediators of bone resorpti on during the initial stage of osteoid removal prior to osteoclast attachme nt. To investigate the mechanism of bone loss following estrogen deficiency , we examined the effects of estrogen on osteoblast synthesis of MMPs and t issue inhibitor of metalloproteinases (TIMPs), Immunolocalization in mouse bone samples ex vivo and primary mouse osteoblast (MOB) cultures was used t o document the synthesis of mouse interstitial collagenase (MMP-13), strome lysin-l (MMP-3), gelatinase-A (MMP-2), and gelatinase-B (MMP-9). Endosteal bone lining cells from distal femoral head and lumbar vertebral body showed an increase in the pattern of synthesis of stromelysin-l following ovariec tomy, compared with sham-operated controls; the synthesis of other MMPs was unaffected. The expression of all classes of MMPs and TIMP-1 and TIMP-2 by MOB in culture was demonstrated by reverse transcriptase-polymerase chain reaction, Following the withdrawal of 17 beta-estradiol, MOB cultures showe d a significant increase in the number of cells synthesizing stromelysin-l; this effect was enhanced by stimulation with either interleukin-l or inter leukin-6. Northern blot analysis showed only a slight increase in stromelys in-l mRNA message following the withdrawal of 17 beta-estradiol, Our data s how an unexpected up-regulation of stromelysin-l synthesis by osteoblasts b oth in vivo and in vitro following estrogen withdrawal. Although this effec t was not reflected in a significant change in stromelysin-1 mRNA expressio n in vitro, there is evidence to suggest a role for this enzyme in the earl y stages of bone loss during the pathogenesis of osteoporosis.