Mouse cathepsin K: cDNA cloning and predominant expression of the gene in osteoclasts, and in some hypertrophying chondrocytes during mouse development

Rantakokko, Juho; Aro, Hannu T.; Savontaus, Mikko; Vuorio, Eero

doi:10.1016/0014-5793(96)00907-6

Cited by 98 publications

(64 citation statements)

References 31 publications

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“…No signal was obtained that corresponded with Cat K, consistent with the relatively low degree of expression of this gene in these tissues, as demonstrated by the results of Fig. 3 (Rantakokko et al, 1996). Cmpd B, the nonbasic selective Cat S inhibitor ( Fig.…”

Section: Evaluation Of In Vivo Cathepsin Inhibition Profilesupporting

confidence: 75%

Effect of Cathepsin K Inhibitor Basicity on in Vivo Off-Target Activities

Desmarais

Black²,

Oballa³

et al. 2007

Mol Pharmacol

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Cathepsin K is a lysosomal cysteine protease that is a pharmacological target for the treatment of osteoporosis. Previous studies showed that basic, lipophilic cathepsin K inhibitors are lysosomotropic and have greater activities in cell-based assays against cathepsin K, as well as the physiologically important lysosomal cysteine cathepsins B, L, and S, than expected based on their potencies against these isolated enzymes. Long-term administration of the basic cathepsin K inhibitors N- (1-(((cyanomethyl) -006235) and balicatib to rats at a supratherapeutic dose of 500 mg/kg/day for 4 weeks resulted in increased tissue protein levels of cathepsin B and L but had no effect on cathepsin B and L message. This is attributed to the inhibitor engagement of these off-target enzymes and their stabilization to proteolytic degradation. No such increase in these tissue cathepsins was detected at the same dose of, a potent nonbasic cathepsin K inhibitor with a similar off-target profile, although all three inhibitors provided similar plasma exposures. Using an activity-based probe, 125 I-BIL-DMK, in vivo inhibition of cathepsins B, L, and S was detected in tissues of mice given a single oral dose of L-006235 and balicatib, but not in mice given L-873724. In each case, similar tissue levels were achieved by all three compounds, thereby demonstrating the in vivo cathepsin selectivity of L-873724. In conclusion, basic cathepsin K inhibitors demonstrate increased off-target cysteine cathepsin activities than their nonbasic analogs and potentially have a greater risk of adverse effects associated with inhibition of these cathepsins.The CA1 family of human papain-like cysteine proteases comprises 11 members. These enzymes are collectively known as cathepsins, a name which is derived from the Greek kathepsein, to digest. Being largely lysosomal enzymes, cathepsins have acidic pH activity and stability optima. These enzymes are synthesized as preproenzymes, the mature proteins sharing between 25 and 80% sequence identity (Lecaille et al., 2002;Turk et al., 2003). Cathepsin K (Cat K) is highly and somewhat specifically expressed in osteoclasts, the multinucleated giant cells of hematopoietic origin that are responsible for the normal physiological process of bone resorption. Cat K destroys the organic fraction of bone through its potent collagenase activity, this process taking place in the acidic pit between the osteoclast and the bone surface and also intracellularly within lysosomes of the osteoclast (Saftig et al., 1998). A large volume of genetic and pharmacological data points to a pivotal role for Cat K in bone resorption, and Cat K inhibitors are presently being evaluated in clinical trials as a treatment of osteoporosis, a disease characterized by an imbalance of bone resorption over bone formation (performed by osteoblasts) (Deaton and Tavares, 2005;Grabowskal et al., 2005;Yasuda et al., 2005;Boyce et al., 2006;Close et al., 2006). Both physiological and pathological roles have been identified for the remaining 10 ...

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Section: Evaluation Of In Vivo Cathepsin Inhibition Profilesupporting

confidence: 75%

Effect of Cathepsin K Inhibitor Basicity on in Vivo Off-Target Activities

Desmarais

Black²,

Oballa³

et al. 2007

Mol Pharmacol

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“…by osteoclastic cells (22,46). Since collagenase 3 is produced by osteoblastic cells but not by osteoclasts, Cbfa1-mediated induction of collagenase 3 expression in fully differentiated osteoblasts could be a critical step in the initiation of the resorptive process, acting in concert with the subsequent participation of an osteoclastic protease like gelatinase B or cathepsin K (58,61). In this regard, of interest is the recent finding that collagenase-3 is an activator of progelatinase B, which should be consistent with the possibility that these enzymes can form a proteolytic cascade in vivo during bone remodeling processes (36).…”

Section: Discussionmentioning

confidence: 99%

Collagenase 3 Is a Target of Cbfa1, a Transcription Factor of the runt Gene Family Involved in Bone Formation

Jiménez

Balbı́n²,

López

et al. 1999

Molecular and Cellular Biology

285

201

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Collagenase 3 (MMP-13) is a recently identified member of the matrix metalloproteinase (MMP) gene family that is expressed at high levels in diverse human carcinomas and in articular cartilage from arthritic patients. In addition to its expression in pathological conditions, collagenase 3 has been detected in osteoblasts and hypertrophic chondrocytes during fetal ossification. In this work, we have evaluated the possibility that Cbfa1 (core binding factor 1), a transcription factor playing a major role in the expression of osteoblastic specific genes, is involved in the expression of collagenase 3 during bone formation. We have functionally characterized a Cbfa motif present in the promoter region of collagenase 3 gene and demonstrated, by cotransfection experiments and gel mobility shift assays, that this element is involved in the inducibility of the collagenase 3 promoter by Cbfa1 in osteoblastic and chondrocytic cells. Furthermore, overexpression of Cbfa1 in osteoblastic cells unable to produce collagenase 3 leads to the expression of this gene after stimulation with transforming growth factor ␤. Finally, we show that mutant mice deficient in Cbfa1, lacking mature osteoblasts but containing hypertrophic chondrocytes which are also a major source of collagenase 3, do not express this protease during fetal development. These results provide in vivo evidence that collagenase 3 is a target of the transcriptional activator Cbfa1 in these cells. On the basis of these transcriptional regulation studies, together with the potent proteolytic activity of collagenase 3 on diverse collagenous and noncollagenous bone and cartilage components, we proposed that this enzyme may play a key role in the process of bone formation and remodeling.

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“…It is mainly expressed in osteoclasts (10 -12) but occurs also in activated chondrocytes (5,(13)(14)(15) and in synovial fibroblasts of patients suffering from rheumatoid arthritis (16). Konttinen et al (15) detected the pH in the immediate surrounding of degraded cartilage areas in osteoarthritic lesions to be between pH 6.2 and 5.5.…”

mentioning

confidence: 99%

Cathepsins B, K, and L Are Regulated by a Defined Collagen Type II Peptide via Activation of Classical Protein Kinase C and p38 MAP Kinase in Articular Chondrocytes

Ruettger

Schueler

Mollenhauer

et al. 2008

Journal of Biological Chemistry

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Degradation of the extracellular matrix (ECM) is a prominent feature in osteoarthritis (OA), which is mainly because of the imbalance between anabolic and catabolic processes in chondrocytes resulting in cartilage and bone destruction. Various proteases act in concert to degrade matrix components, e.g. type II collagen, MMPs, ADAMTS, and cathepsins. Protease-generated collagen fragments may foster the destructive process. However, the signaling pathways associated with the action of collagen fragments on chondrocytes have not been clearly defined. The present data demonstrate that the N-terminal telopeptide of collagen type II enhances expression of cathepsins B, K, and L in articular chondrocytes at mRNA, protein, and activity levels, mediated at least in part through extracellular calcium. We also demonstrate that the induction is associated with the activation of protein kinase C and p38 MAP kinase.

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Mouse cathepsin K: cDNA cloning and predominant expression of the gene in osteoclasts, and in some hypertrophying chondrocytes during mouse development

Cited by 98 publications

References 31 publications

Effect of Cathepsin K Inhibitor Basicity on in Vivo Off-Target Activities

Effect of Cathepsin K Inhibitor Basicity on in Vivo Off-Target Activities

Collagenase 3 Is a Target of Cbfa1, a Transcription Factor of the runt Gene Family Involved in Bone Formation

Cathepsins B, K, and L Are Regulated by a Defined Collagen Type II Peptide via Activation of Classical Protein Kinase C and p38 MAP Kinase in Articular Chondrocytes

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