Functions of Cathepsin K in Bone Resorption

Säftig, Paul; Hunziker, Ernst B.; Everts, Vincent; Jones, S. J.; Boyde, A.; Wehmeyer, Olaf; Suter, A.; Figura, Kurt Von

doi:10.1007/0-306-46826-3_32

Cited by 115 publications

(28 citation statements)

References 26 publications

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“…Cathepsin K exhibits strong collagenolytic activity with a broad pH optimum and is selectively expressed by osteoclasts and giant cell tumors [47]. In addition, cathepsin-K KO mice exhibit osteopetrosis and a short stature [48], a similar phenotype of autosomal recessive osteochondrodysplasia caused by a mutation in cathepsin K [49]. Thus, cathepsin K is considered to be critical for bone resorption.…”

Section: Involvement Of Mmps In Bone Resorptionmentioning

confidence: 97%

Joint Diseases and Matrix Metalloproteinases: A Role for MMP-13

Takaishi

Kimura²,

Dalal

et al. 2008

CPB

246

210

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The role of matrix metalloproteinases in disease has been investigated over the last two decades. A focus on this family of proteases is particularly emphasized in two major arthritides in humans, osteoarthritis and rheumatoid arthritis. Early work described the presence of multiple MMP family members in the joint of the disease state and recent advances in the development of new knockout mice and disease models have allowed investigators to directly test the role of the MMP proteases in arthritis. MMP-13 is expressed by chondrocytes and synovial cells in human OA and RA and is thought to play a critical role in cartilage destruction. The recent development of an MMP-13 knockout mouse has documented the important role for this enzyme in cartilage formation and further studies under disease conditions promise to reveal the function of this enzyme in disease pathology. This review describes a body of research that supports the development of novel selective MMP-13 inhibitors with the hope of developing these compounds in clinical trials for the treatment of arthritis.

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Section: Involvement Of Mmps In Bone Resorptionmentioning

confidence: 97%

Joint Diseases and Matrix Metalloproteinases: A Role for MMP-13

Takaishi

Kimura²,

Dalal

et al. 2008

CPB

246

210

View full text Add to dashboard Cite

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“…Bone resorption occurs within the sealing zone that is formed by an actin ring structure containing podosomes that anchors osteoclasts to the bone surface and is characterized by dissipation and degradation of two components of the bone matrix, the inorganic mineral crystalline hydroxyapatite and the organic collagen rich matrix. Proteases, namely cathepsin K, are responsible for the degradation of the organic bone matrix, releasing collagen fragments [5]. …”

Section: Introductionmentioning

confidence: 99%

Effects of ω3- and ω6-Polyunsaturated Fatty Acids on RANKL-Induced Osteoclast Differentiation of RAW264.7 Cells: A Comparative in Vitro Study

et al. 2014

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Polyunsaturated fatty acids (PUFAs) have been reported to have an anabolic effect on bone in vivo, but comparative studies to identify inhibitors of osteoclast formation amongst ω3- and ω6-PUFAs are still lacking. Here we assessed the effects of the ω3-PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the ω6-PUFAs, arachidonic acid (AA) and γ-linolenic acid (GLA) on a RAW264.7 osteoclast differentiation model. The effects of PUFAs on RANKL-induced osteoclast formation were evaluated by counting tartrate resistant acid phosphatase (TRAP)-positive multinucleated cells. PUFAs significantly inhibited RANKL-induced osteoclast formation in a dose-dependent manner with AA- and DHA-mediated inhibition being the strongest. Furthermore, RANKL-induced mRNA- and protein expression of the key osteoclastogenic genes cathepsin K and TRAP were inhibited by AA and more potently by DHA. Owing to the attenuated osteoclastogenesis by DHA and AA, actin ring formation and bone resorptive activity of these cells as evaluated on bone-mimetic plates were severely compromised. Hence, of the tested PUFAs, AA and DHA were found to be the most effective in inhibiting RANKL-induced osteoclast formation with the latter providing the strongest inhibitory effects. Collectively, the data indicates that these PUFAs may play an important role in regulating bone diseases characterized by excessive osteoclast activity.

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“…CatK knockout mice showed an osteopetrotic phenotype associated with a severe impairment of resorptive activity of osteoclasts [53]. Several lines of evidence have shown that osteoclastic lesions are important to the development of bone metastases [12].…”

Section: Discussionmentioning

confidence: 99%

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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Functions of Cathepsin K in Bone Resorption

Cited by 115 publications

References 26 publications

Joint Diseases and Matrix Metalloproteinases: A Role for MMP-13

Joint Diseases and Matrix Metalloproteinases: A Role for MMP-13

Effects of ω3- and ω6-Polyunsaturated Fatty Acids on RANKL-Induced Osteoclast Differentiation of RAW264.7 Cells: A Comparative in Vitro Study

Inhibition of Prostate Cancer Skeletal Metastases by Targeting Cathepsin K

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