Design of potent and selective human cathepsin K inhibitors that span the active site

Thompson, Scott K.; Halbert, S. M.; Bossard, Mary J.; Tomaszek, Thaddeus A.; Levy, Mark A.; Zhao, Baoguang; Smith, Ward W.; Abdel-Meguid, Sherin S.; Janson, Cheryl A.; D'Alessio, Karla; McQueney, Michael S.; Amegadzie, Bernard Y.; Hanning, Charles R.; DesJarlais, Renée L.; Briand, Jacques; Sarkar, Soumalya; Huddleston, Michael J.; Ijames, Carl F.; Carr, Steven A.; Garnes, Keith T.; Shu, Arthur Y. L.; Heys, J. Richard; Bradbeer, Jeremy N.; Zembryki, Denise; Lee-Rykaczewski, L; James, Ian E.; Lark, Michael W.; Drake, Fred H.; Gowen, Maxine; Gleason, John G.; Veber, Daniel F.

doi:10.1073/pnas.94.26.14249

Cited by 127 publications

(90 citation statements)

References 25 publications

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“…The cathepsin K inhibitor, SB331750, has been recently reported to retard bone matrix degradation, which resulted in prevention of OVX-induced loss in trabecular structure (Lark et al, 2002). It has also been reported that cathepsin K knockout mice show a phenotype similar to that seen in patients with pycnodysostosis (Hsu et al, 1999;Thompson et al, 1997). All these results provide convincing evidence for the actual involvement of H ϩ -ATPase and cathepsin K in the demineralization of apatite crystals and subsequent degradation of bone matrix in the subosteoclastic microenvironment.…”

Section: Role Of Vacuolar-type Hmentioning

confidence: 67%

Differentiation and functions of osteoclasts and odontoclasts in mineralized tissue resorption

Sasaki

2003

Microscopy Res & Technique

121

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The differentiation and functions of osteoclasts (OC) are regulated by osteoblast-derived factors such as receptor activator of NFKB ligand (RANKL) that stimulates OC formation, and a novel secreted member of the TNF receptor superfamily, osteoprotegerin (OPG), that negatively regulates osteoclastogenesis. In examination of the preosteoclast (pOC) culture, pOCs formed without any additives expressed tartrate-resistant acid phosphatase (TRAP), but showed little resorptive activity. pOC treated with RANKL became TRAP-positive OC, which expressed intense vacuolar-type H(+)-ATPase and exhibited prominent resorptive activity. Such effects of RANKL on pOC were completely inhibited by addition of OPG. OPG inhibited ruffled border formation in mature OC and reduced their resorptive activity, and also induced apoptosis of some OC. Although OPG administration significantly reduced trabecular bone loss in the femurs of ovariectomized (OVX) mice, the number of TRAP-positive OC in OPG-administered OVX mice was not significantly decreased. Rather, OPG administration caused the disappearance of ruffled borders and decreased H(+)-ATPase expression in most OC. OPG deficiency causes severe osteoporosis. We also examined RANKL localization and OC induction in periodontal ligament (PDL) during experimental movement of incisors in OPG-deficient mice. Compared to wild-type OPG (+/+) littermates, after force application, TRAP-positive OC were markedly increased in the PDL and alveolar bone was severely destroyed in OPG-deficient mice. In both wild-type and OPG-deficient mice, RANKL expression in osteoblasts and fibroblasts became stronger by force application. These in vitro and in vivo studies suggest that RANKL and OPG are important regulators of not only the terminal differentiation of OC but also their resorptive function. To determine resorptive functions of OC, we further examined the effects of specific inhibitors of H(+)-ATPase, bafilomycin A1, and lysosomal cysteine proteinases (cathepsins), E-64, on the ultrastructure, expression of these enzymes and resorptive functions of cultured OC. In bafilomycin A1-treated cultures, OC lacked ruffled borders, and H(+)-ATPase expression and resorptive activity were significantly diminished. E-64 treatment did not affect the ultrastructure and the expression of enzyme molecules in OC, but significantly reduced resorption lacuna formation, by inhibition of cathepsin activity. Lastly, we examined the expression of H(+)-ATPase, cathepsin K, and matrix metalloproteinase-9 in odontoclasts (OdC) during physiological root resorption in human deciduous teeth, and found that there were no differences in the expression of these molecules between OC and OdC. RANKL was also detected in stromal cells located on resorbing dentine surfaces. This suggests that there is a common mechanism in cellular resorption of mineralized tissues such as bone and teeth.

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Section: Role Of Vacuolar-type Hmentioning

confidence: 67%

Differentiation and functions of osteoclasts and odontoclasts in mineralized tissue resorption

Sasaki

2003

Microscopy Res & Technique

121

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“…CK-/ -mice are viable and fertile but display profound osteosclerotic abnormalities. These animals, as well as the wild-type C57BL / 6J mice, were bred and sacrificed at various ages (5,7,12, and 28 days after birth). Skulls were fixed with 2.5% formaldehyde in 0.1 M sodium cacodylate buffer (pH 7.4).…”

Section: Preparation Of Sectionsmentioning

confidence: 99%

The Regulation of Bone Resorption in Tooth Formation and Eruption Processes in Mouse Alveolar Crest Devoid of Cathepsin K

Okaji

Sakai

et al. 2003

J Pharmacol Sci

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Abstract. Osteoclastic bone resorption has recently been implicated in the tooth formation and eruption in alveolar bone. Cathepsin K (CK) is a cysteine proteinase expressed predominantly in osteoclasts and is believed to play a critical role in degradation of bone matrix proteins. Here we present evidence that the alveolar bone resorption is essential for the tooth formation and that eruption proceeds normally in CK-deficient (CK-/ -) mice. Radiographic and histological analyses revealed that the alveolar bone from these animals had no significant abnormalities during the tooth development between 5 and 28 days after birth. The tooth crown was normally erupted through the alveolar bone layer at 28 days after birth. The number of tartrate-resistant acid phosphatase-positive multinuclear cells in the alveolar bone around the tooth germ was apparently increased in 5-day-old CK-/ -mice compared with age-matched littermates. More important, however, the immunohistochemical localization of matrix metalloproteinase-9 (MMP-9) was clearly increased in the CK-/ -osteoclasts. In contrast, no significant difference in the immunoreactivity for cathepsin D was observed between the CK-/-osteoclasts and the wild-type ones. These results indicate that CK-/ -osteoclasts are fully differentiated and are capable of degrading the organic phase of alveolar bone during the tooth formation and eruption, which may result from the compensatory action by MMP-9 increasingly expressed in the osteoclasts.

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“…Importantly, CatK expression in bone metastases was significantly greater than primary PCa, while CatK in normal prostate tissues was negative [40] suggesting that CatK may play a role in PCa skeletal metastases . Recently, a selective human CatK inhibitor has been described to potently inhibit osteoclast resorption both in vitro and in vivo [41][42][43][44]. In this study, we report that CatK contributes to PCa-induced osteoclast activity at bone metastatic sites, and inhibition of CatK by a selective inhibitor may prevent the establishment and progression of PCa in bone.…”

Section: Introductionmentioning

confidence: 61%

Inhibition of Prostate Cancer Skeletal Metastases by Targeting Cathepsin K

Zhang¹

2009

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. (From -To) REPORT DATE (DD-MM-YYYY) 01-05-2009 REPORT TYPE Annual DATES COVERED PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER University of PittsburghPittsburgh, PA 15260 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research And Material Command Fort Detrick, Maryland SPONSOR/MONITOR'S REPORT 21702-5012 NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for public release; distribution unlimited SUPPLEMENTARY NOTES14. ABSTRACT We have previously shown that CatK is expressed not only by osteoclasts but also by prostate cancer (PCa) cells and stromal cells. Zoledronic acid (ZA), a bisphosphonate which exerts beneficial effects in PCa patients with bone metastases, reduces both pain and skeletal related events. We hypothesized that combination of a bisphosphonate with the CatK inhibitor, through different inhibitory mechanisms, could diminish PCa progression in vivo. Accordingly, PCa C4-2B cells were inoculated into the tibiae of SCID mice. The mice were randomized into the following treatment groups (n=10/group): ZA, CatK inhibitor, the combination of ZA and CatK inhibitor, and saline vehicle alone. Test drugs were initiated at 4 weeks after the tumor cell inoculation and treatments were continued for 8 weeks.We found that CatK inhibitor significantly reduced skeletal tumor burden as determined by both tumor volume vs soft tissue volume ratio and serum PSA levels. In contrast, ZA less effectively diminished the skeletal tumor volume. ZA failed to decrease PSA levels. Importantly, combinations of the two agents were more effective in decreasing tumor volume than any single agent. Using one PCa cell line, we show for the first time that a CatK inhibitor diminishes PCa growth in bone and the inhibitory effects are enhanced in combination with ZA. More cell lines need to be tested. SUBJECT TERMS IntroductionThe subject of this study is: "Inhibition of prostate cancer (PCa) skeletal metastases by targeting cathepsin K". PCa is the most frequently diagnosed cancer in men and the second leading cause of cancer...

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Design of potent and selective human cathepsin K inhibitors that span the active site

Cited by 127 publications

References 25 publications

Differentiation and functions of osteoclasts and odontoclasts in mineralized tissue resorption

Differentiation and functions of osteoclasts and odontoclasts in mineralized tissue resorption

The Regulation of Bone Resorption in Tooth Formation and Eruption Processes in Mouse Alveolar Crest Devoid of Cathepsin K

Inhibition of Prostate Cancer Skeletal Metastases by Targeting Cathepsin K

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