Regulation of collagenolytic cysteine protease synthesis by estrogen in osteoclasts

In ovariectomized (Ovx) mice, collagenolytic cysteine protease (CCP) activi ty in calvaria significantly increased 7 days after ovariectomy and was abo ut 50% of that observed in sham-operated (Sham) mice 3 weeks later. In Ovx mice, subcutaneously (s.c.) administered estradiol-17 beta (E2) (10 mu g/kg ) for 2 weeks led to a decrease in CCP activity in calvaria to the level ob served in Sham mice. In Ovx mice, though the amount of cathepsin L increase d more than that of cathepsin K, cathepsin K and cathepsin L content increa sed by 200-400% compared with the Sham mice; cathepsin K was detected in la rger amounts than cathepsin L in calvaria from both Sham and Ovx mice. The amounts of cathepsin K and cathepsin L in Ovx mice were reduced to the valu es seen with Sham mice after administration (s.c.) of E2 (10 mu g/kg) for 2 weeks. In mouse calvarial organ culture, the increase of CCP activity and release of hydroxyproline, an indicator of degradation of type-I collagen, in the presence of 1 alpha,25-(OH)(2)D-3, parathyroid hormone, interleukin (IL)-1 alpha, IL-6, or tumor necrosis factor-a! was suppressed by E2 (10(-9 )-10(-7) M). In all cases, secretion of both cathepsin K and cathepsin L we re suppressed by E2. In osteoclasts, expression of cathepsin K and cathepsi n L was suppressed by E2 at the mRNA level. Cathepsin B was detected faintl y or not at all. These results suggest that synthesis of cathepsin K and ca thepsin L was negatively regulated by E2 at the mRNA level. In Ovx mice, de ficiency of E2 resulted in an augmentation of cathepsin K and cathepsin L s ynthesis, and the cathepsins might share roles in bone resorption in vivo. (C) 2000 Elsevier Science Inc. All rights reserved.