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The selective cathepsin K inhibitor MIV-711 attenuates joint pathology in experimental animal models of osteoarthritis
MIV-711 is a highly potent and selective cathepsin K inhibitor. The current article summarizes the therapeutic effects of MIV-711 on joint pathology in rabbits subjected to anterior cruciate ligament transection (ACLT), and the prophylactic effects on joint pathology in dogs subjected to partial med...
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| Published in: | Journal of translational medicine 2018-03, Vol.16 (1), p.56-16, Article 56 |
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| creator | Lindström, Erik Rizoska, Biljana Tunblad, Karin Edenius, Charlotte Bendele, Alison M Maul, Don Larson, Michael Shah, Neha Yoder Otto, Valerie Jerome, Chris Grabowska, Urszula |
| description | MIV-711 is a highly potent and selective cathepsin K inhibitor. The current article summarizes the therapeutic effects of MIV-711 on joint pathology in rabbits subjected to anterior cruciate ligament transection (ACLT), and the prophylactic effects on joint pathology in dogs subjected to partial medial meniscectomy, two surgical models of osteoarthritis (OA).
Starting 1 week after surgery, rabbits were dosed daily via oral gavage with either MIV-711 or vehicle (n = 7/group) for 7 weeks. The four treatment groups were: (1) sham + vehicle; (2) ACLT + vehicle; (3) ACLT + MIV-711, 30 µmol/kg and (4) ACLT + MIV-711, 100 µmol/kg. Subchondral bone and articular cartilage structures were assessed by µCT, histomorphometry, and scoring. Dogs subjected to partial medial meniscectomy received either MIV-711 (30 µmol/kg) or vehicle (n = 15/group) via oral gavage once daily, starting 1 day before meniscectomy, for 28 days. Cartilage degradation was assessed at the macroscopic and microscopic levels. The exposures of MIV-711 were assessed in both studies and biomarkers reflecting bone resorption (HP-1 in rabbits, CTX-I in dogs) and cartilage degradation (CTX-II) were measured.
In ACLT rabbits, MIV-711 decreased HP-1 levels by up to 72% (p |
| doi_str_mv | 10.1186/s12967-018-1425-7 |
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Starting 1 week after surgery, rabbits were dosed daily via oral gavage with either MIV-711 or vehicle (n = 7/group) for 7 weeks. The four treatment groups were: (1) sham + vehicle; (2) ACLT + vehicle; (3) ACLT + MIV-711, 30 µmol/kg and (4) ACLT + MIV-711, 100 µmol/kg. Subchondral bone and articular cartilage structures were assessed by µCT, histomorphometry, and scoring. Dogs subjected to partial medial meniscectomy received either MIV-711 (30 µmol/kg) or vehicle (n = 15/group) via oral gavage once daily, starting 1 day before meniscectomy, for 28 days. Cartilage degradation was assessed at the macroscopic and microscopic levels. The exposures of MIV-711 were assessed in both studies and biomarkers reflecting bone resorption (HP-1 in rabbits, CTX-I in dogs) and cartilage degradation (CTX-II) were measured.
In ACLT rabbits, MIV-711 decreased HP-1 levels by up to 72% (p < 0.001) and CTX-II levels by up to 74% (p < 0.001) compared to ACLT vehicle controls. ACLT surgery significantly reduced the total thickness of the subchondral bone plate and reduced trabecular bone volume in the femur and tibia. These effects were reversed by MIV-711. ACLT resulted in cartilage thickening, which was attenuated by MIV-711. MIV-711 did not affect osteophyte formation or Mankin scores. In dogs, MIV-711 reduced CTX-I and CTX-II levels by 86% (p < 0.001) and 80% (p < 0.001), respectively. Synovial CTX-II levels were reduced by 55-57% (p < 0.001) compared to baseline. MIV-711-treated animals had 25-37% lower macroscopic scores in the femur condyles and 13-33% lower macroscopic scores in the tibial plateaus.
MIV-711 prevents subchondral bone loss and partially attenuates cartilage pathology in two animal models of OA. These beneficial effects of MIV-711 on joint pathology are observed in conjunction with decreases in bone and cartilage biomarkers that have been shown to be clinically attainable in human. The data support the further development of MIV-711 for the treatment of OA.</description><identifier>ISSN: 1479-5876</identifier><identifier>EISSN: 1479-5876</identifier><identifier>DOI: 10.1186/s12967-018-1425-7</identifier><identifier>PMID: 29523155</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Analysis ; Animals ; Anterior Cruciate Ligament ; Anterior Cruciate Ligament Injuries - drug therapy ; Biomarkers - blood ; Biomarkers - urine ; Bone Resorption - pathology ; Care and treatment ; Cartilage, Articular - diagnostic imaging ; Cartilage, Articular - drug effects ; Cartilage, Articular - pathology ; Cathepsin K ; Cathepsin K - antagonists & inhibitors ; Cathepsins ; CTX-I ; CTX-II ; Cysteine Proteinase Inhibitors - blood ; Cysteine Proteinase Inhibitors - pharmacokinetics ; Cysteine Proteinase Inhibitors - pharmacology ; Cysteine Proteinase Inhibitors - therapeutic use ; Diagnosis ; Disease Models, Animal ; Dogs ; Female ; Gene expression ; Genetic aspects ; Health aspects ; HP-1 ; Joints (Anatomy) ; Joints - diagnostic imaging ; Joints - drug effects ; Joints - pathology ; Male ; Organic Chemicals ; Osteoarthritis ; Osteoarthritis - blood ; Osteoarthritis - diagnostic imaging ; Osteoarthritis - drug therapy ; Osteoarthritis - pathology ; Principal Component Analysis ; Rabbits ; Radionuclide imaging ; Subchondral bone ; Treatment outcome</subject><ispartof>Journal of translational medicine, 2018-03, Vol.16 (1), p.56-16, Article 56</ispartof><rights>COPYRIGHT 2018 BioMed Central Ltd.</rights><rights>The Author(s) 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c532t-8b9e12959c4bb0215b83a0be74001de6b41f6ab9efd144cbad32765309c981423</citedby><cites>FETCH-LOGICAL-c532t-8b9e12959c4bb0215b83a0be74001de6b41f6ab9efd144cbad32765309c981423</cites><orcidid>0000-0002-9946-7174</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845353/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845353/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29523155$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lindström, Erik</creatorcontrib><creatorcontrib>Rizoska, Biljana</creatorcontrib><creatorcontrib>Tunblad, Karin</creatorcontrib><creatorcontrib>Edenius, Charlotte</creatorcontrib><creatorcontrib>Bendele, Alison M</creatorcontrib><creatorcontrib>Maul, Don</creatorcontrib><creatorcontrib>Larson, Michael</creatorcontrib><creatorcontrib>Shah, Neha</creatorcontrib><creatorcontrib>Yoder Otto, Valerie</creatorcontrib><creatorcontrib>Jerome, Chris</creatorcontrib><creatorcontrib>Grabowska, Urszula</creatorcontrib><title>The selective cathepsin K inhibitor MIV-711 attenuates joint pathology in experimental animal models of osteoarthritis</title><title>Journal of translational medicine</title><addtitle>J Transl Med</addtitle><description>MIV-711 is a highly potent and selective cathepsin K inhibitor. The current article summarizes the therapeutic effects of MIV-711 on joint pathology in rabbits subjected to anterior cruciate ligament transection (ACLT), and the prophylactic effects on joint pathology in dogs subjected to partial medial meniscectomy, two surgical models of osteoarthritis (OA).
Starting 1 week after surgery, rabbits were dosed daily via oral gavage with either MIV-711 or vehicle (n = 7/group) for 7 weeks. The four treatment groups were: (1) sham + vehicle; (2) ACLT + vehicle; (3) ACLT + MIV-711, 30 µmol/kg and (4) ACLT + MIV-711, 100 µmol/kg. Subchondral bone and articular cartilage structures were assessed by µCT, histomorphometry, and scoring. Dogs subjected to partial medial meniscectomy received either MIV-711 (30 µmol/kg) or vehicle (n = 15/group) via oral gavage once daily, starting 1 day before meniscectomy, for 28 days. Cartilage degradation was assessed at the macroscopic and microscopic levels. The exposures of MIV-711 were assessed in both studies and biomarkers reflecting bone resorption (HP-1 in rabbits, CTX-I in dogs) and cartilage degradation (CTX-II) were measured.
In ACLT rabbits, MIV-711 decreased HP-1 levels by up to 72% (p < 0.001) and CTX-II levels by up to 74% (p < 0.001) compared to ACLT vehicle controls. ACLT surgery significantly reduced the total thickness of the subchondral bone plate and reduced trabecular bone volume in the femur and tibia. These effects were reversed by MIV-711. ACLT resulted in cartilage thickening, which was attenuated by MIV-711. MIV-711 did not affect osteophyte formation or Mankin scores. In dogs, MIV-711 reduced CTX-I and CTX-II levels by 86% (p < 0.001) and 80% (p < 0.001), respectively. Synovial CTX-II levels were reduced by 55-57% (p < 0.001) compared to baseline. MIV-711-treated animals had 25-37% lower macroscopic scores in the femur condyles and 13-33% lower macroscopic scores in the tibial plateaus.
MIV-711 prevents subchondral bone loss and partially attenuates cartilage pathology in two animal models of OA. These beneficial effects of MIV-711 on joint pathology are observed in conjunction with decreases in bone and cartilage biomarkers that have been shown to be clinically attainable in human. The data support the further development of MIV-711 for the treatment of OA.</description><subject>Analysis</subject><subject>Animals</subject><subject>Anterior Cruciate Ligament</subject><subject>Anterior Cruciate Ligament Injuries - drug therapy</subject><subject>Biomarkers - blood</subject><subject>Biomarkers - urine</subject><subject>Bone Resorption - pathology</subject><subject>Care and treatment</subject><subject>Cartilage, Articular - diagnostic imaging</subject><subject>Cartilage, Articular - drug effects</subject><subject>Cartilage, Articular - pathology</subject><subject>Cathepsin K</subject><subject>Cathepsin K - antagonists & inhibitors</subject><subject>Cathepsins</subject><subject>CTX-I</subject><subject>CTX-II</subject><subject>Cysteine Proteinase Inhibitors - blood</subject><subject>Cysteine Proteinase Inhibitors - pharmacokinetics</subject><subject>Cysteine Proteinase Inhibitors - pharmacology</subject><subject>Cysteine Proteinase Inhibitors - therapeutic use</subject><subject>Diagnosis</subject><subject>Disease Models, Animal</subject><subject>Dogs</subject><subject>Female</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>HP-1</subject><subject>Joints (Anatomy)</subject><subject>Joints - diagnostic imaging</subject><subject>Joints - drug effects</subject><subject>Joints - pathology</subject><subject>Male</subject><subject>Organic Chemicals</subject><subject>Osteoarthritis</subject><subject>Osteoarthritis - blood</subject><subject>Osteoarthritis - diagnostic imaging</subject><subject>Osteoarthritis - drug therapy</subject><subject>Osteoarthritis - pathology</subject><subject>Principal Component Analysis</subject><subject>Rabbits</subject><subject>Radionuclide imaging</subject><subject>Subchondral bone</subject><subject>Treatment outcome</subject><issn>1479-5876</issn><issn>1479-5876</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNptkktr3DAUhU1pSdI0P6CbIujaqZ62tSmE0MfQhG7SboUe12MNtmUkZUj-fTV1GzIQtJC4OvfTPeJU1XuCLwnpmk-JUNm0NSZdTTgVdfuqOiO8lbXo2ub1s_Np9TalHcaUCy5PqlMqBWVEiLNqfzcASjCCzX4PyOo8wJL8jH4gPw_e-Bwiut38rltCkM4Z5nudIaFd8HNGS5GHMWwfixjBwwLRTzBnPSI9-6lsU3AwJhR6FFKGoGMeos8-vave9HpMcPFvP69-ff1yd_29vvn5bXN9dVNbwWiuOyOheBTScmMwJcJ0TGMDLceYOGgMJ32ji6h3hHNrtGO0bQTD0squfAk7rzYr1wW9U0sZT8dHFbRXfwshblWZydsRFJbEcJCNw7jnTLe6E6IxjmMqC9q1hfV5ZS33ZgJni9GoxyPo8c3sB7UNeyU6LphgBfBxBWx1ec_PfSgyO_lk1ZXgDWGC4oPq8gVVWQ4mb8MMvS_1owayNtgYUorQP41EsDrkRK05USUn6pATdfDy4bmXp47_wWB_AH43uY0</recordid><startdate>20180309</startdate><enddate>20180309</enddate><creator>Lindström, Erik</creator><creator>Rizoska, Biljana</creator><creator>Tunblad, Karin</creator><creator>Edenius, Charlotte</creator><creator>Bendele, Alison M</creator><creator>Maul, Don</creator><creator>Larson, Michael</creator><creator>Shah, Neha</creator><creator>Yoder Otto, Valerie</creator><creator>Jerome, Chris</creator><creator>Grabowska, Urszula</creator><general>BioMed Central Ltd</general><general>BioMed Central</general><general>BMC</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-9946-7174</orcidid></search><sort><creationdate>20180309</creationdate><title>The selective cathepsin K inhibitor MIV-711 attenuates joint pathology in experimental animal models of osteoarthritis</title><author>Lindström, Erik ; Rizoska, Biljana ; Tunblad, Karin ; Edenius, Charlotte ; Bendele, Alison M ; Maul, Don ; Larson, Michael ; Shah, Neha ; Yoder Otto, Valerie ; Jerome, Chris ; Grabowska, Urszula</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c532t-8b9e12959c4bb0215b83a0be74001de6b41f6ab9efd144cbad32765309c981423</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Analysis</topic><topic>Animals</topic><topic>Anterior Cruciate Ligament</topic><topic>Anterior Cruciate Ligament Injuries - drug therapy</topic><topic>Biomarkers - blood</topic><topic>Biomarkers - urine</topic><topic>Bone Resorption - pathology</topic><topic>Care and treatment</topic><topic>Cartilage, Articular - diagnostic imaging</topic><topic>Cartilage, Articular - drug effects</topic><topic>Cartilage, Articular - pathology</topic><topic>Cathepsin K</topic><topic>Cathepsin K - antagonists & inhibitors</topic><topic>Cathepsins</topic><topic>CTX-I</topic><topic>CTX-II</topic><topic>Cysteine Proteinase Inhibitors - blood</topic><topic>Cysteine Proteinase Inhibitors - pharmacokinetics</topic><topic>Cysteine Proteinase Inhibitors - pharmacology</topic><topic>Cysteine Proteinase Inhibitors - therapeutic use</topic><topic>Diagnosis</topic><topic>Disease Models, Animal</topic><topic>Dogs</topic><topic>Female</topic><topic>Gene expression</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>HP-1</topic><topic>Joints (Anatomy)</topic><topic>Joints - diagnostic imaging</topic><topic>Joints - drug effects</topic><topic>Joints - pathology</topic><topic>Male</topic><topic>Organic Chemicals</topic><topic>Osteoarthritis</topic><topic>Osteoarthritis - blood</topic><topic>Osteoarthritis - diagnostic imaging</topic><topic>Osteoarthritis - drug therapy</topic><topic>Osteoarthritis - pathology</topic><topic>Principal Component Analysis</topic><topic>Rabbits</topic><topic>Radionuclide imaging</topic><topic>Subchondral bone</topic><topic>Treatment outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lindström, Erik</creatorcontrib><creatorcontrib>Rizoska, Biljana</creatorcontrib><creatorcontrib>Tunblad, Karin</creatorcontrib><creatorcontrib>Edenius, Charlotte</creatorcontrib><creatorcontrib>Bendele, Alison M</creatorcontrib><creatorcontrib>Maul, Don</creatorcontrib><creatorcontrib>Larson, Michael</creatorcontrib><creatorcontrib>Shah, Neha</creatorcontrib><creatorcontrib>Yoder Otto, Valerie</creatorcontrib><creatorcontrib>Jerome, Chris</creatorcontrib><creatorcontrib>Grabowska, Urszula</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Journal of translational medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lindström, Erik</au><au>Rizoska, Biljana</au><au>Tunblad, Karin</au><au>Edenius, Charlotte</au><au>Bendele, Alison M</au><au>Maul, Don</au><au>Larson, Michael</au><au>Shah, Neha</au><au>Yoder Otto, Valerie</au><au>Jerome, Chris</au><au>Grabowska, Urszula</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The selective cathepsin K inhibitor MIV-711 attenuates joint pathology in experimental animal models of osteoarthritis</atitle><jtitle>Journal of translational medicine</jtitle><addtitle>J Transl Med</addtitle><date>2018-03-09</date><risdate>2018</risdate><volume>16</volume><issue>1</issue><spage>56</spage><epage>16</epage><pages>56-16</pages><artnum>56</artnum><issn>1479-5876</issn><eissn>1479-5876</eissn><abstract>MIV-711 is a highly potent and selective cathepsin K inhibitor. The current article summarizes the therapeutic effects of MIV-711 on joint pathology in rabbits subjected to anterior cruciate ligament transection (ACLT), and the prophylactic effects on joint pathology in dogs subjected to partial medial meniscectomy, two surgical models of osteoarthritis (OA).
Starting 1 week after surgery, rabbits were dosed daily via oral gavage with either MIV-711 or vehicle (n = 7/group) for 7 weeks. The four treatment groups were: (1) sham + vehicle; (2) ACLT + vehicle; (3) ACLT + MIV-711, 30 µmol/kg and (4) ACLT + MIV-711, 100 µmol/kg. Subchondral bone and articular cartilage structures were assessed by µCT, histomorphometry, and scoring. Dogs subjected to partial medial meniscectomy received either MIV-711 (30 µmol/kg) or vehicle (n = 15/group) via oral gavage once daily, starting 1 day before meniscectomy, for 28 days. Cartilage degradation was assessed at the macroscopic and microscopic levels. The exposures of MIV-711 were assessed in both studies and biomarkers reflecting bone resorption (HP-1 in rabbits, CTX-I in dogs) and cartilage degradation (CTX-II) were measured.
In ACLT rabbits, MIV-711 decreased HP-1 levels by up to 72% (p < 0.001) and CTX-II levels by up to 74% (p < 0.001) compared to ACLT vehicle controls. ACLT surgery significantly reduced the total thickness of the subchondral bone plate and reduced trabecular bone volume in the femur and tibia. These effects were reversed by MIV-711. ACLT resulted in cartilage thickening, which was attenuated by MIV-711. MIV-711 did not affect osteophyte formation or Mankin scores. In dogs, MIV-711 reduced CTX-I and CTX-II levels by 86% (p < 0.001) and 80% (p < 0.001), respectively. Synovial CTX-II levels were reduced by 55-57% (p < 0.001) compared to baseline. MIV-711-treated animals had 25-37% lower macroscopic scores in the femur condyles and 13-33% lower macroscopic scores in the tibial plateaus.
MIV-711 prevents subchondral bone loss and partially attenuates cartilage pathology in two animal models of OA. These beneficial effects of MIV-711 on joint pathology are observed in conjunction with decreases in bone and cartilage biomarkers that have been shown to be clinically attainable in human. The data support the further development of MIV-711 for the treatment of OA.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>29523155</pmid><doi>10.1186/s12967-018-1425-7</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-9946-7174</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of translational medicine, 2018-03, Vol.16 (1), p.56-16, Article 56 |
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| subjects | Analysis Animals Anterior Cruciate Ligament Anterior Cruciate Ligament Injuries - drug therapy Biomarkers - blood Biomarkers - urine Bone Resorption - pathology Care and treatment Cartilage, Articular - diagnostic imaging Cartilage, Articular - drug effects Cartilage, Articular - pathology Cathepsin K Cathepsin K - antagonists & inhibitors Cathepsins CTX-I CTX-II Cysteine Proteinase Inhibitors - blood Cysteine Proteinase Inhibitors - pharmacokinetics Cysteine Proteinase Inhibitors - pharmacology Cysteine Proteinase Inhibitors - therapeutic use Diagnosis Disease Models, Animal Dogs Female Gene expression Genetic aspects Health aspects HP-1 Joints (Anatomy) Joints - diagnostic imaging Joints - drug effects Joints - pathology Male Organic Chemicals Osteoarthritis Osteoarthritis - blood Osteoarthritis - diagnostic imaging Osteoarthritis - drug therapy Osteoarthritis - pathology Principal Component Analysis Rabbits Radionuclide imaging Subchondral bone Treatment outcome |
| title | The selective cathepsin K inhibitor MIV-711 attenuates joint pathology in experimental animal models of osteoarthritis |
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