Repeated oral administration of a cathepsin K inhibitor significantly suppresses bone resorption in exercising horses with evidence of increased bone formation and maintained bone turnover

Hussein, Hayam; Dulin, Jennifer N.; Smanik, Lauren E.; Drost, Wm Tod; Russell, Duncan S.; Wellman, Maxey L.; Bertone, Alicia L.

doi:10.1111/jvp.12368

Cited by 7 publications

(13 citation statements)

References 40 publications

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“…Therefore, it was hypothesized that if there were a systemic effect of tiludronate or clodronate administration in the horse at the routine clinical dose administered, it would have been detected in the current study. In addition, a recent study evaluating the effect of the bone resorption inhibitor cathepsin K, which does not fully prevent osteoclastic resorption as bisphosphonates have been shown to do [ 31 ], was performed with groups of 6 horses, with significant differences found [ 32 ]. Therefore, we conclude that the lack of changes identified in the current study, especially related to the re-biopsy results and effects on a model of bone healing, are truly reflective of an overall lack of influence of these drugs on bone remodeling kinetics in the horse.…”

Section: Discussionmentioning

confidence: 99%

Tiludronate and clodronate do not affect bone structure or remodeling kinetics over a 60 day randomized trial

et al. 2018

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BackgroundTiludronate and clodronate are FDA-approved bisphosphonate drug therapies for navicular disease in horses. Although clinical studies have determined their ability to reduce lameness associated with skeletal disorders in horses, data regarding the effect on bone structure and remodeling is lacking. Additionally, due to off-label use of these drugs in young performance horses, effects on bone in young horses need to be investigated. Therefore, the purpose of this randomized, experimental pilot study was to determine the effect of tiludronate and clodronate on normal bone cells, structure and remodeling after 60 days in clinically normal, young horses. Additionally, the effect of clodronate on bone healing 60 days after an induced defect was investigated.ResultsAll horses tolerated surgery well, with no post-surgery lameness and all acquired biopsies being adequate for analyses. Overall, tiludronate and clodronate did not significantly alter any bone structure or remodeling parameters, as evaluated by microCT and dynamic histomorphometry. Tiludronate did not extensively impact bone formation or resorption parameters as evaluated by static histomorphometry. Similarly, clodronate did not affect bone formation or resorption after 60 days. Sixty days post-defect, healing was minimally affected by clodronate.ConclusionsTiludronate and clodronate do not appear to significantly impact bone tissue on a structural or cellular level using standard dose and administration schedules.

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Section: Discussionmentioning

confidence: 99%

Tiludronate and clodronate do not affect bone structure or remodeling kinetics over a 60 day randomized trial

et al. 2018

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“…VEL-0230 was used in a mass concentration of 0.3 μg/ml of culture media to achieve the lowest molar concentration of 1μM. However, the maximum plasma concentration of VEL-0230 did not exceed 0.1μg/ml, achieved using an oral dose regimen of 4mg/kg of body weight q7 days in healthy exercising horses, and by which resulted in a marked decline in bone resorption without altering the number of osteoclasts as confirmed by TRAP staining of bone biopsies and subsequent analysis [8,10] .…”

Section: Discussionmentioning

confidence: 98%

“…Biopsy samples were collected from six of the horses from the Tuber coxae (TC), a non-weight-bearing bone, and the proximal phalanx (P1), a weight-bearing bone, as previously described [10] . Horses were randomly assigned to left or right TC and forelimb P1.…”

Section: Bone Biopsymentioning

confidence: 99%

“…We have investigated the pharmacokinetics of a potent CatK inhibitor, VEL-0230, in healthy exercising horses for future therapeutic application in equine patients with osteo-inflammatory conditions [8] . Cathepsin K inhibition ameliorated the inflammatory response of equine bone marrow mononuclear cells stimulated by Toll like receptors (TLR) -4 and TLR-9 ligands in vitro along with evidence of suppressed bone resorption and increased bone formation in vivo due to repeated VEL-0230 administration in healthy exercising horses [9,10] . The precise role of CatK in the immune system is unclear and maybe attributed, in part, to the location and tight integration between the bone and bone marrow.…”

Section: Introductionmentioning

confidence: 99%

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Cathepsin K Localizes to Equine Bone In Vivo and Inhibits Bone Marrow Stem and Progenitor Cells Differentiation In Vitro

Hussein

Boyaka

Dulin

et al. 2017

JSRM

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Selective inhibition of Cathepsin K (CatK) has a promising therapeutic potential for diseases associated with bone loss and osseous inflammation, such as osteoarthritis, periodontitis, and osteoporosis. In horses, stress-related bone injuries are common and accompanied by bone pain and inflammation resulting in excessive bone resorption and periostitis. VEL-0230 is a highly selective inhibitor of CatK that significantly decreased bone resorption and increased bone formation biomarkers. The goal of this study was to demonstrate the presence of CatK in equine bone and a simultaneous influence on the bone marrow cellular components including function and differentiation. Our objectives were: 1) to investigate the tissue localization of CatK protein in equine bone using immunohistochemistry, and 2) to determine the effect of CatK inhibition on osteoclastogenic, chondrogenic and osteogenic differentiation potential of equine stem and progenitor cells in vitro using histochemical staining and differentiation-related gene expression analyses. Bone biopsies, harvested from the tuber coxae and proximal phalanx of six healthy horses, were processed for immunostaining against CatK. Sternal bone marrow aspirates were cultured in 0, 1, 10, or 100 μM of VEL-0230 and subsequent staining scoring and gene expression analyses performed. All cells morphologically characterized as osteoclasts and moderate number of active bone lining osteoblasts stained positive for CatK. Histochemical staining and gene expression analyses revealed a significant increase in the osteoclastogenic, chondrogenic and osteogenic differentiation potential of equine bone marrow cells, which was VEL-0230-concentration dependent for the latter two. These results suggested that CatK inhibition may have anabolic effects on bone and cartilage regeneration that may be explained as a feedback response to CatK depletion. In conclusion, the use of CatK inhibition to reduce inflammation and associated bone resorption in equine osseous disorders may offer advantages to other therapeutics that would require further study.

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“…At present, research results demonstrated the strong antiresorptive activity and high selectivity of some inhibitors 10 . Furthermore, several Cat K inhibitors under preclinical or clinical investigation for indications such as bone metastases, rheumatoid arthritis or osteoporosis have made optimistic and positive progresses 11–13 .…”

Section: Introductionmentioning

confidence: 99%

Advances in the discovery of cathepsin K inhibitors on bone resorption

Lü

Wang

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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Cathepsin K (Cat K), highly expressed in osteoclasts, is a cysteine protease member of the cathepsin lysosomal protease family and has been of increasing interest as a target of medicinal chemistry efforts for its role in bone matrix degradation. Inhibition of the Cat K enzyme reduces bone resorption and thus, has rendered the enzyme as an attractive target for anti-resorptive osteoporosis therapy. Over the past decades, considerable efforts have been made to design and develop highly potent, excellently selective and orally applicable Cat K inhibitors. These inhibitors are derived from synthetic compounds or natural products, some of which have passed preclinical studies and are presently in clinical trials at different stages of advancement. In this review, we briefly summarised the historic development of Cat K inhibitors and discussed the relationship between structures of inhibitors and active sites in Cat K for the purpose of guiding future development of inhibitors.

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Repeated oral administration of a cathepsin K inhibitor significantly suppresses bone resorption in exercising horses with evidence of increased bone formation and maintained bone turnover

Cited by 7 publications

References 40 publications

Tiludronate and clodronate do not affect bone structure or remodeling kinetics over a 60 day randomized trial

Tiludronate and clodronate do not affect bone structure or remodeling kinetics over a 60 day randomized trial

Cathepsin K Localizes to Equine Bone In Vivo and Inhibits Bone Marrow Stem and Progenitor Cells Differentiation In Vitro

Advances in the discovery of cathepsin K inhibitors on bone resorption

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