Regulation of collagenolytic cysteine protease synthesis by estrogen in osteoclasts.
In ovariectomized (Ovx) mice, collagenolytic cysteine protease (CCP) activity in calvaria significantly increased 7 days after ovariectomy and was about 50% of that observed in sham-operated (Sham) mice 3 weeks later. In Ovx mice, subcutaneously (s.c.) administered estradiol-17beta (E2) (10 microg/kg) for 2 weeks led to a decrease in CCP activity in calvaria to the level observed in Sham mice. In Ovx mice, though the amount of cathepsin L increased more than that of cathepsin K, cathepsin K and cathepsin L content increased by 200-400% compared with the Sham mice; cathepsin K was detected in larger 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 values seen with Sham mice after administration (s.c.) of E2 (10 microg/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 1alpha,25-(OH)(2)D(3), parathyroid hormone, interleukin (IL)-1alpha, IL-6, or tumor necrosis factor-alpha was suppressed by E2 (10(-9)-10(-7) M). In all cases, secretion of both cathepsin K and cathepsin L were suppressed by E2. In osteoclasts, expression of cathepsin K and cathepsin L was suppressed by E2 at the mRNA level. Cathepsin B was detected faintly or not at all. These results suggest that synthesis of cathepsin K and cathepsin L was negatively regulated by E2 at the mRNA level. In Ovx mice, deficiency of E2 resulted in an augmentation of cathepsin K and cathepsin L synthesis, and the cathepsins might share roles in bone resorption in vivo.
Furuyama
N
N
Discovery Research Laboratory, Takeda Chemical Industries, Ltd., 17-85, Juso-honmachi 2-chome, Yodogawa-ku, 532-8686, Osaka, Japan. FURUYAMA_NAOKI@takeda.co.jp
Fujisawa
Y
Y
D000818:Animals; D015153:Blotting, Western; D001842:Bone and Bones / Q000378:metabolism / Q000502:physiology; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D017931:DNA Primers / Q000737:chemistry; D010450:Endopeptidases; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006909:Hydroxyproline / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009924:Organ Culture Techniques; D010010:Osteoclasts / Q000187:drug effects* / Q000201:enzymology; D010052:Ovariectomy; D010053:Ovary / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism
D017931:DNA Primers; D012333:RNA, Messenger; D004958:Estradiol; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D056657:Cathepsin K; C534132:Ctsk protein, mouse; D006909:Hydroxyproline