Impaired bone resorption in cathepsin K-deficient mice is partially compensated for by enhanced osteoclastogenesis and increased expression of other proteases via an increased RANKL/OPG ratio

• Published in: Bone (New York, N.Y.) Vol. 36; no. 1; pp. 159 - 172
• Main Authors: Kiviranta, Riku, Morko, Jukka, Alatalo, Sari L., NicAmhlaoibh, Roisin, Risteli, Juha, Laitala-Leinonen, Tiina, Vuorio, Eero
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.01.2005; Elsevier Science
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Bone histomorphometry; Bone remodeling; Bone Resorption - genetics; Bone turnover markers; Carrier Proteins - metabolism; Cathepsin K; Cathepsins - genetics; Cathepsins - physiology; Cell Differentiation; Diseases of the osteoarticular system; Female; Fundamental and applied biological sciences. Psychology; Glycoproteins - metabolism; Knockout; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Osteoclasts; Osteoclasts - cytology; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Tumor Necrosis Factor - metabolism; RNA, Messenger - genetics; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Bone histomorphometry; Osteoclasts; Bone remodeling; Bone turnover markers; Knockout; Growth; Cysteine endopeptidases; Diseases of the osteoarticular system; Osteoclast; Matrix metalloproteinase 14; Mechanism; Prevention; Osteopetrosis; Osteoblast; Bone matrix; Osteochondrodysplasia; Age; Quantitative analysis; Human; Cathepsin K; Radiodiagnosis; Enzyme; Critically ill; Rodentia; Media; Resorption; Gene expression; Genetic disease; Peptidases; Vertebrata; Phenotype; Mammalia; Mouse; Animal; Hydrolases; Medical imagery; Computerized axial tomography; Bone; Differentiation
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2004.09.020

Previous reports indicate that mice deficient for cathepsin K (Ctsk), a key protease in osteoclastic bone resorption, develop osteopetrosis due to their inability to properly degrade organic bone matrix. Some features of the phenotype of Ctsk knockout mice, however, suggest the presence of mechanisms by which Ctsk-deficient mice compensate for the lack of cathepsin K. To study these mechanisms in detail, we generated Ctsk-deficient (Ctsk−/−) mice and analyzed them at the age of 2, 7, and 12 months using peripheral quantitative computed tomography, histomorphometry, resorption marker measurements, osteoclast and osteoblast differentiation cultures, and gene expression analyses. The present study verified the previously published osteopetrotic features of Ctsk-deficient mice. However, these changes did not exacerbate during aging indicating the absence of Ctsk to have its most severe effects during the rapid growth period. Resorption markers ICTP and CTX were decreased in the media of Ctsk−/− osteoclasts cultured on bone slices indicating impaired bone resorption. Ctsk−/− mice exhibited several mechanisms attempting to compensate for Ctsk deficiency. The number of osteoclasts in trabecular bone was significantly increased in Ctsk−/− mice compared to controls, as was the number of osteoclast precursors in bone marrow. The mRNA levels for receptor activator of nuclear factor κB ligand (RANKL) in Ctsk−/− bones were increased resulting in increased RANKL/OPG ratio favoring osteoclastogenesis. In addition, expression of mRNAs of osteoclastic enzymes (MMP-9, TRACP) and for osteoblastic proteases (MMP-13, MMP-14) were increased in Ctsk−/− mice compared to controls. Impaired osteoclastic bone resorption in Ctsk−/− mice results in activation of osteoblastic cells to produce increased amounts of other proteolytic enzymes and RANKL in vivo. We suggest that increased RANKL expression mediates enhanced osteoclastogenesis and increased protease expression by osteoclasts. These observations underline the important role of osteoblastic cells in regulation of osteoclast activity and bone turnover.