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Cysteine proteinase inhibitors regulate human and mouse osteoclastogenesis by interfering with RANK signaling.

Journal article
Authors Fredrik Strålberg
Petra Henning
Inger Gjertsson
Bert Kindlund
Pedro P C Souza
Emma Persson
Magnus Abrahamson
Franciszek Kasprzykowski
Anders Grubb
Ulf H Lerner
Published in FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume 27
Issue 7
Pages 2687-701
ISSN 1530-6860
Publication year 2013
Published at Institute of Medicine, Department of Rheumatology and Inflammation Research
Centre for Bone and Arthritis Research
Pages 2687-701
Language en
Keywords Animals, Antigens, CD14, metabolism, Blotting, Western, Bone Marrow Cells, cytology, drug effects, metabolism, Cell Differentiation, drug effects, Cells, Cultured, Cystatin C, pharmacology, Cysteine Proteinase Inhibitors, pharmacology, Gene Expression, drug effects, Humans, Macrophages, cytology, drug effects, metabolism, Mice, Mice, Inbred C57BL, Monocytes, cytology, drug effects, metabolism, NFATC Transcription Factors, genetics, metabolism, Osteoclasts, cytology, drug effects, metabolism, Proto-Oncogene Proteins c-fos, genetics, metabolism, RANK Ligand, pharmacology, Receptor Activator of Nuclear Factor-kappa B, metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, drug effects
Subject categories Endocrinology


The cysteine proteinase inhibitor cystatin C inhibited RANKL-stimulated osteoclast formation in mouse bone marrow macrophage cultures, an effect associated with decreased mRNA expression of Acp5, Calcr, Ctsk, Mmp9, Itgb3, and Atp6i, without effect on proliferation or apoptosis. The effects were concentration dependent with half-maximal inhibition at 0.3 μM. Cystatin C also inhibited osteoclast formation when RANKL-stimulated osteoclasts were cultured on bone, leading to decreased formation of resorption pits. RANKL-stimulated cells retained characteristics of phagocytotic macrophages when cotreated with cystatin C. Three other cysteine proteinase inhibitors, cystatin D, Z-RLVG-CHN2 (IC50 0.1 μM), and E-64 (IC50 3 μM), also inhibited osteoclast formation in RANKL-stimulated macrophages. In addition, cystatin C, Z-RLVG-CHN2, and E-64 inhibited osteoclastic differentiation of RANKL-stimulated CD14(+) human monocytes. The effect by cystatin C on differentiation of bone marrow macrophages was exerted at an early stage after RANKL stimulation and was associated with early (4 h) inhibition of c-Fos expression and decreased protein and nuclear translocation of c-Fos. Subsequently, p52, p65, IκBα, and Nfatc1 mRNA were decreased. Cystatin C was internalized in osteoclast progenitors, a process requiring RANKL stimulation. These data show that cystatin C inhibits osteoclast differentiation and formation by interfering intracellularly with signaling pathways downstream RANK.

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