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Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo
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| Zeitschriftentitel: | Journal of Bone and Mineral Research |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , , , |
| In: | Journal of Bone and Mineral Research, 12, 1997, 9, S. 1396-1406 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Oxford University Press (OUP)
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| Schlagwörter: |
| author_facet |
Votta, Bartholomew J. Levy, Mark A. Badger, Alison Bradbeer, Jeremy Dodds, Robert A. James, Ian E. Thompson, Scott Bossard, Mary J. Carr, Thomas Connor, Janice R. Tomaszek, Thaddeus A. Szewczuk, Lawrence Drake, Fred H. Veber, Daniel F. Gowen, Maxine Votta, Bartholomew J. Levy, Mark A. Badger, Alison Bradbeer, Jeremy Dodds, Robert A. James, Ian E. Thompson, Scott Bossard, Mary J. Carr, Thomas Connor, Janice R. Tomaszek, Thaddeus A. Szewczuk, Lawrence Drake, Fred H. Veber, Daniel F. Gowen, Maxine |
|---|---|
| author |
Votta, Bartholomew J. Levy, Mark A. Badger, Alison Bradbeer, Jeremy Dodds, Robert A. James, Ian E. Thompson, Scott Bossard, Mary J. Carr, Thomas Connor, Janice R. Tomaszek, Thaddeus A. Szewczuk, Lawrence Drake, Fred H. Veber, Daniel F. Gowen, Maxine |
| spellingShingle |
Votta, Bartholomew J. Levy, Mark A. Badger, Alison Bradbeer, Jeremy Dodds, Robert A. James, Ian E. Thompson, Scott Bossard, Mary J. Carr, Thomas Connor, Janice R. Tomaszek, Thaddeus A. Szewczuk, Lawrence Drake, Fred H. Veber, Daniel F. Gowen, Maxine Journal of Bone and Mineral Research Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo Orthopedics and Sports Medicine Endocrinology, Diabetes and Metabolism |
| author_sort |
votta, bartholomew j. |
| spelling |
Votta, Bartholomew J. Levy, Mark A. Badger, Alison Bradbeer, Jeremy Dodds, Robert A. James, Ian E. Thompson, Scott Bossard, Mary J. Carr, Thomas Connor, Janice R. Tomaszek, Thaddeus A. Szewczuk, Lawrence Drake, Fred H. Veber, Daniel F. Gowen, Maxine 0884-0431 1523-4681 Oxford University Press (OUP) Orthopedics and Sports Medicine Endocrinology, Diabetes and Metabolism http://dx.doi.org/10.1359/jbmr.1997.12.9.1396 <jats:title>Abstract</jats:title> <jats:p>We have shown previously that cathepsin K, a recently identified member of the papain superfamily of cysteine proteases, is expressed selectively in osteoclasts and is the predominant cysteine protease in these cells. Based upon its abundant cell type-selective expression, potent endoprotease activity at low pH and cellular localization at the bone interface, cathepsin K has been proposed to play a specialized role in osteoclast-mediated bone resorption. In this study, we evaluated a series of peptide aldehydes and demonstrated that they are potent cathepsin K inhibitors. These compounds inhibited osteoclast-mediated bone resorption in fetal rat long bone (FRLB) organ cultures in vitro in a concentration-dependent manner. Selected compounds were also shown to inhibit bone resorption in a human osteoclast-mediated assay in vitro. Cbz-Leu-Leu-Leu-H (in vitro enzyme inhibition Ki,app = 1.4 nM) inhibited parathyroid hormone (PTH)-stimulated resorption in the FRLB assay with an IC-50 of 20 nM and inhibited resorption by isolated human osteoclasts cultured on bovine cortical bone slices with an IC-50 of 100 nM. In the adjuvant-arthritic (AA) rat model, in situ hybridization studies demonstrated high levels of cathepsin K expression in osteoclasts at sites of extensive bone loss in the distal tibia. Cbz-Leu-Leu-Leu-H (30 mg/kg, intraperitoneally) significantly reduced this bone loss, as well as the associated hind paw edema. In the thyroparathyriodectomized rat model, Cbz-Leu-Leu-Leu-H inhibited the increase in blood ionized calcium induced by a 6 h infusion of PTH. These data indicate that inhibitors of cathepsin K are effective at reducing osteoclast-mediated bone resorption and may have therapeutic potential in diseases of excessive bone resorption such as rheumatoid arthritis or osteoporosis.</jats:p> Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo Journal of Bone and Mineral Research |
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| title |
Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo |
| title_unstemmed |
Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo |
| title_full |
Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo |
| title_fullStr |
Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo |
| title_full_unstemmed |
Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo |
| title_short |
Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo |
| title_sort |
peptide aldehyde inhibitors of cathepsin k inhibit bone resorption both in vitro and in vivo |
| topic |
Orthopedics and Sports Medicine Endocrinology, Diabetes and Metabolism |
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http://dx.doi.org/10.1359/jbmr.1997.12.9.1396 |
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1997 |
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1396-1406 |
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<jats:title>Abstract</jats:title>
<jats:p>We have shown previously that cathepsin K, a recently identified member of the papain superfamily of cysteine proteases, is expressed selectively in osteoclasts and is the predominant cysteine protease in these cells. Based upon its abundant cell type-selective expression, potent endoprotease activity at low pH and cellular localization at the bone interface, cathepsin K has been proposed to play a specialized role in osteoclast-mediated bone resorption. In this study, we evaluated a series of peptide aldehydes and demonstrated that they are potent cathepsin K inhibitors. These compounds inhibited osteoclast-mediated bone resorption in fetal rat long bone (FRLB) organ cultures in vitro in a concentration-dependent manner. Selected compounds were also shown to inhibit bone resorption in a human osteoclast-mediated assay in vitro. Cbz-Leu-Leu-Leu-H (in vitro enzyme inhibition Ki,app = 1.4 nM) inhibited parathyroid hormone (PTH)-stimulated resorption in the FRLB assay with an IC-50 of 20 nM and inhibited resorption by isolated human osteoclasts cultured on bovine cortical bone slices with an IC-50 of 100 nM. In the adjuvant-arthritic (AA) rat model, in situ hybridization studies demonstrated high levels of cathepsin K expression in osteoclasts at sites of extensive bone loss in the distal tibia. Cbz-Leu-Leu-Leu-H (30 mg/kg, intraperitoneally) significantly reduced this bone loss, as well as the associated hind paw edema. In the thyroparathyriodectomized rat model, Cbz-Leu-Leu-Leu-H inhibited the increase in blood ionized calcium induced by a 6 h infusion of PTH. These data indicate that inhibitors of cathepsin K are effective at reducing osteoclast-mediated bone resorption and may have therapeutic potential in diseases of excessive bone resorption such as rheumatoid arthritis or osteoporosis.</jats:p> |
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| author | Votta, Bartholomew J., Levy, Mark A., Badger, Alison, Bradbeer, Jeremy, Dodds, Robert A., James, Ian E., Thompson, Scott, Bossard, Mary J., Carr, Thomas, Connor, Janice R., Tomaszek, Thaddeus A., Szewczuk, Lawrence, Drake, Fred H., Veber, Daniel F., Gowen, Maxine |
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| description | <jats:title>Abstract</jats:title> <jats:p>We have shown previously that cathepsin K, a recently identified member of the papain superfamily of cysteine proteases, is expressed selectively in osteoclasts and is the predominant cysteine protease in these cells. Based upon its abundant cell type-selective expression, potent endoprotease activity at low pH and cellular localization at the bone interface, cathepsin K has been proposed to play a specialized role in osteoclast-mediated bone resorption. In this study, we evaluated a series of peptide aldehydes and demonstrated that they are potent cathepsin K inhibitors. These compounds inhibited osteoclast-mediated bone resorption in fetal rat long bone (FRLB) organ cultures in vitro in a concentration-dependent manner. Selected compounds were also shown to inhibit bone resorption in a human osteoclast-mediated assay in vitro. Cbz-Leu-Leu-Leu-H (in vitro enzyme inhibition Ki,app = 1.4 nM) inhibited parathyroid hormone (PTH)-stimulated resorption in the FRLB assay with an IC-50 of 20 nM and inhibited resorption by isolated human osteoclasts cultured on bovine cortical bone slices with an IC-50 of 100 nM. In the adjuvant-arthritic (AA) rat model, in situ hybridization studies demonstrated high levels of cathepsin K expression in osteoclasts at sites of extensive bone loss in the distal tibia. Cbz-Leu-Leu-Leu-H (30 mg/kg, intraperitoneally) significantly reduced this bone loss, as well as the associated hind paw edema. In the thyroparathyriodectomized rat model, Cbz-Leu-Leu-Leu-H inhibited the increase in blood ionized calcium induced by a 6 h infusion of PTH. These data indicate that inhibitors of cathepsin K are effective at reducing osteoclast-mediated bone resorption and may have therapeutic potential in diseases of excessive bone resorption such as rheumatoid arthritis or osteoporosis.</jats:p> |
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| spelling | Votta, Bartholomew J. Levy, Mark A. Badger, Alison Bradbeer, Jeremy Dodds, Robert A. James, Ian E. Thompson, Scott Bossard, Mary J. Carr, Thomas Connor, Janice R. Tomaszek, Thaddeus A. Szewczuk, Lawrence Drake, Fred H. Veber, Daniel F. Gowen, Maxine 0884-0431 1523-4681 Oxford University Press (OUP) Orthopedics and Sports Medicine Endocrinology, Diabetes and Metabolism http://dx.doi.org/10.1359/jbmr.1997.12.9.1396 <jats:title>Abstract</jats:title> <jats:p>We have shown previously that cathepsin K, a recently identified member of the papain superfamily of cysteine proteases, is expressed selectively in osteoclasts and is the predominant cysteine protease in these cells. Based upon its abundant cell type-selective expression, potent endoprotease activity at low pH and cellular localization at the bone interface, cathepsin K has been proposed to play a specialized role in osteoclast-mediated bone resorption. In this study, we evaluated a series of peptide aldehydes and demonstrated that they are potent cathepsin K inhibitors. These compounds inhibited osteoclast-mediated bone resorption in fetal rat long bone (FRLB) organ cultures in vitro in a concentration-dependent manner. Selected compounds were also shown to inhibit bone resorption in a human osteoclast-mediated assay in vitro. Cbz-Leu-Leu-Leu-H (in vitro enzyme inhibition Ki,app = 1.4 nM) inhibited parathyroid hormone (PTH)-stimulated resorption in the FRLB assay with an IC-50 of 20 nM and inhibited resorption by isolated human osteoclasts cultured on bovine cortical bone slices with an IC-50 of 100 nM. In the adjuvant-arthritic (AA) rat model, in situ hybridization studies demonstrated high levels of cathepsin K expression in osteoclasts at sites of extensive bone loss in the distal tibia. Cbz-Leu-Leu-Leu-H (30 mg/kg, intraperitoneally) significantly reduced this bone loss, as well as the associated hind paw edema. In the thyroparathyriodectomized rat model, Cbz-Leu-Leu-Leu-H inhibited the increase in blood ionized calcium induced by a 6 h infusion of PTH. These data indicate that inhibitors of cathepsin K are effective at reducing osteoclast-mediated bone resorption and may have therapeutic potential in diseases of excessive bone resorption such as rheumatoid arthritis or osteoporosis.</jats:p> Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo Journal of Bone and Mineral Research |
| spellingShingle | Votta, Bartholomew J., Levy, Mark A., Badger, Alison, Bradbeer, Jeremy, Dodds, Robert A., James, Ian E., Thompson, Scott, Bossard, Mary J., Carr, Thomas, Connor, Janice R., Tomaszek, Thaddeus A., Szewczuk, Lawrence, Drake, Fred H., Veber, Daniel F., Gowen, Maxine, Journal of Bone and Mineral Research, Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo, Orthopedics and Sports Medicine, Endocrinology, Diabetes and Metabolism |
| title | Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo |
| title_full | Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo |
| title_fullStr | Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo |
| title_full_unstemmed | Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo |
| title_short | Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo |
| title_sort | peptide aldehyde inhibitors of cathepsin k inhibit bone resorption both in vitro and in vivo |
| title_unstemmed | Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo |
| topic | Orthopedics and Sports Medicine, Endocrinology, Diabetes and Metabolism |
| url | http://dx.doi.org/10.1359/jbmr.1997.12.9.1396 |