Accelerated Turnover of Metaphyseal Trabecular Bone in Mice Overexpressing Cathepsin K

Kiviranta, Riku; Morko, Jukka; Uusitalo, Hannele; Aro, Hannu T.; Vuorio, Eero; Rantakokko, Juho

doi:10.1359/jbmr.2001.16.8.1444

Cited by 124 publications

(82 citation statements)

References 42 publications

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“…This indicates that cathepsin K slows the progression of cartilage degradation at the initial stage of OA. Cathepsin K is a papain-like cysteine protease and is shown to be responsible for the main proteolytic activity that occurs during osteoclastic bone resorption (24,25). The cathepsin K gene was considered to be exclusively expressed in osteoclasts.…”

Section: Discussionmentioning

confidence: 99%

Down‐regulation of cathepsin K in synovium leads to progression of osteoarthritis in rabbits

Takahashi

Iwasaki

Kawa

et al. 2009

Arthritis & Rheumatism

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Objective. The hypothesis of this study was that synovial factors playing a pivotal role in the pathogenesis of osteoarthritis (OA) and thus gene expression in the synovium would be altered at the initial stage of OA. The aims of this study were to identify the candidate genes in synovium related to OA initiation, to evaluate cartilage degeneration after knockdown of the gene using small interfering RNA (siRNA) gene silencing in the knee joints at the initial stage of OA, and to determine the potential role of the knocked-down gene in OA initiation.Methods. Genes overexpressed in synovium at the initial stage of disease in a rabbit model of anterior cruciate ligament transection (ACLT)-induced OA were identified using the suppression subtractive hybridization technique and differential screening. Candidate gene expression in the synovium of the knees of rabbits with OA was manipulated with electroporation-assisted siRNA transduction 4 times before and after operation. Four weeks after surgery, histologic analysis was performed.Results. Cathepsin K gene and protein expression was significantly up-regulated in synovium at the initial stage of OA in rabbits. Down-regulation of cathepsin K in synovium at the initial stage of OA significantly accelerated cartilage degeneration.Conclusion. These results indicate that cathepsin K plays a protective role in cartilage degeneration at the initial stage of OA. We believe that the current results obtained from models of the early phase of OA will provide useful information for developing a novel strategy to prevent disease progression.

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Section: Discussionmentioning

confidence: 99%

Down‐regulation of cathepsin K in synovium leads to progression of osteoarthritis in rabbits

Takahashi

Iwasaki

Kawa

et al. 2009

Arthritis & Rheumatism

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“…In addition to many unique functions and characteristic microscopic features in particular, osteoclasts are also positive for the G protein-coupled calcitonin receptor (CTR) (2), the serine protease cathepsin K (CTSK) (3), and a subcellular structure known as the F-actin ring that is associated with bone resorption activity (4,5). Osteoclasts differentiate from hematopoietic precursors of monocyte/macrophage lineages (1), through the effects of receptor activator of NFB ligand (RANKL) present on the surface of stromal cells and osteoblasts (6,7).…”

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confidence: 99%

MCP-1-induced Human Osteoclast-like Cells Are Tartrate-resistant Acid Phosphatase, NFATc1, and Calcitonin Receptor-positive but Require Receptor Activator of NFκB Ligand for Bone Resorption

Kim

Day

Selinger

et al. 2006

Journal of Biological Chemistry

135

113

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“…Cathepsin K is highly expressed in osteoclasts near the ruffled border membrane and has been shown to participate in osteoclast-mediated degradation of the sub-osteoclastic collagenous bone matrix (31)(32)(33)(34)(35)(36). Cathepsin K-overexpressing mice showed an increased turnover of metaphyseal trabecular bone (37), whereas cathepsin K knock-out mice displayed an osteopetrotic phenotype because of impaired matrix degradation (38 -40). Besides cathepsin K, also cathepsins B, H, L, and S are expressed by osteoclasts and could participate in bone resorption (35,(41)(42)(43).…”

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confidence: 99%

Proteolytic Excision of a Repressive Loop Domain in Tartrate-resistant Acid Phosphatase by Cathepsin K in Osteoclasts

Ljusberg¹,

Wang²,

Lång³

et al. 2005

Journal of Biological Chemistry

125

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Tartrate-resistant acid phosphatase (TRAP) is a metallophosphoesterase participating in osteoclast-mediated bone turnover. Activation of TRAP is associated with the redox state of the di-iron metal center as well as with limited proteolytic cleavage in an exposed loop domain. The cysteine proteinases cathepsin B, L, K, and S as well as the matrix metalloproteinase-2, -9, -13, and -14 are expressed by osteoclasts and/or other bone cells and have been implicated in the turnover of bone and cartilage. To identify proteases that could act as activators of TRAP in bone, we report here that cathepsins K and L, in contrast to the matrix metalloproteinases, efficiently cleaved and activated recombinant TRAP in vitro. Activation of TRAP by cathepsin K/L was because of increases in catalytic activity, substrate affinity, and sensitivity to reductants. Processing by cathepsin K occurred sequentially by an initial excision of the loop peptide Gly Tartrate-resistant acid phosphatase (TRAP), 1 also known as type 5 acid phosphatase (EC 3.1.3.2) or uteroferrin, belongs to the purple acid phosphatase (PAP) subfamily of the non-heme dinuclear metallophosphatases (1-3). The metals of the catalytic center of all PAPs consist of a common ferric ion and a divalent metal cation in an active enzyme, where mammalian PAPs characteristically contain a redox-active iron in the M(II) site (4 -6).The TRAP enzyme is abundantly expressed by bone-resorbing cells, osteoclasts, and certain subpopulations of monocytes/ macrophages and dendritic cells (7-10). The precise role of osteoclastic TRAP is not fully understood, but studies on TRAP knock-out mice showed disturbed endochondral ossification with decreased resorptive activity of osteoclasts (11, 12), whereas overexpression of TRAP was associated with increased bone turnover (10). Different functions have been suggested for TRAP, e.g. as an osteopontin phosphatase (13-15), generation of reactive oxygen species (16 -19), iron transport (20 -24), and as a growth/differentiation factor for hematopoietic (25) and osteoblastic (26) cells.Mammalian PAPs are synthesized as 35-37-kDa monomers but are commonly isolated from tissues as proteolytically cleaved two-subunit forms consisting of a 23-kDa N-terminal domain disulfide-linked to a 16-kDa C-terminal domain. The monomeric form exhibits properties of a proenzyme with low phosphatase activity that is converted to a high activity, twosubunit form upon proteolytic cleavage in the intervening loop domain with either serine proteases, e.g. trypsin or chymotrypsin (27), or members of the cathepsin family (28,29). Mutagenesis studies suggested that proteolysis removes or alters repressive interactions between loop amino acids and active site residues because replacement of Asp 146 of the exposed loop domain with Ala resulted in activation of unproteolyzed TRAP (30).Several lines of evidence indicate a role for cathepsin K in bone resorption. Cathepsin K is highly expressed in osteoclasts near the ruffled border membrane and has been shown to participate i...

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Accelerated Turnover of Metaphyseal Trabecular Bone in Mice Overexpressing Cathepsin K

Cited by 124 publications

References 42 publications

Down‐regulation of cathepsin K in synovium leads to progression of osteoarthritis in rabbits

Down‐regulation of cathepsin K in synovium leads to progression of osteoarthritis in rabbits

MCP-1-induced Human Osteoclast-like Cells Are Tartrate-resistant Acid Phosphatase, NFATc1, and Calcitonin Receptor-positive but Require Receptor Activator of NFκB Ligand for Bone Resorption

Proteolytic Excision of a Repressive Loop Domain in Tartrate-resistant Acid Phosphatase by Cathepsin K in Osteoclasts

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