Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis

Conaghan, Philip G.; Bowes, M.A.; Kingsbury,; Brett, Alan; Guillard, G.; Rizoska, Biljana; Sjögren, Niclas; Graham, P. A.; Jansson, Andreas; Wadell, Cecilia; Bethell, Richard C.; Öhd, John

doi:10.7326/m19-0675

Cited by 112 publications

(76 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is encouraging to learn that CatK inhibition could exert obvious chondroprotective effect in preclinical OA models (Connor et al, 2009;McDougall et al, 2010;Hayami et al, 2012;Lindstrom et al, 2018). Furthermore, a novel selective CatK inhibitor MIV-711 by Medivir was recently reflected to reduce bone remodeling and cartilage volume loss but have no impact on pain in OA patients in a Phase-IIa trial (Conaghan et al, 2019). Nevertheless, the structural benefits by CatK inhibition…”

Section: Catk and Skeletal Diseasesmentioning

confidence: 99%

Cathepsin K: The Action in and Beyond Bone

Dai

Chu

et al. 2020

Front. Cell Dev. Biol.

135

View full text Add to dashboard Cite

Cathepsin K (CatK) is one of the most potent proteases in lysosomal cysteine proteases family, of which main function is to mediate bone resorption. Currently, CatK is among the most attractive targets for anti-osteoporosis drug development. Although many pharmaceutical companies are working on the development of selective inhibitors for CatK, there is no FDA approved drug till now. Odanacatib (ODN) developed by Merck & Co. is the only CatK inhibitor candidate which demonstrated high therapeutic efficacy in patients with postmenopausal osteoporosis in Phase III clinical trials. Unfortunately, the development of ODN was finally terminated due to the cardio-cerebrovascular adverse effects. Therefore, it arouses concerns on the undesirable CatK inhibition in non-bone sites. It is known that CatK has far-reaching actions throughout various organs besides bone. Many studies have also demonstrated the involvement of CatK in various diseases beyond the musculoskeletal system. This review not only summarized the functional roles of CatK in bone and beyond bone, but also discussed the potential relevance of the CatK action beyond bone to the adverse effects of inhibiting CatK in non-bone sites.

show abstract

Section: Catk and Skeletal Diseasesmentioning

confidence: 99%

Cathepsin K: The Action in and Beyond Bone

Dai

Chu

et al. 2020

Front. Cell Dev. Biol.

135

View full text Add to dashboard Cite

show abstract

“…The inhibition of CTSs has been widely explored over the last decades in the field of chronic inflammatory diseases [27,37,204,205], cardiovascular diseases [10,19,181], osteoporosis [70][71][72][73], arthritis [28,206], kidney diseases [30][31][32]84], pancreatitis [207], obesity [208][209][210], cancer [25,34,48,74,82,211], neurodegenerative diseases [39,41,184,185,212,213], and many other pathological states. Multiple inhibitors are currently available, ranging from reversible covalent inhibitors to irreversible inhibitors [214][215][216][217][218] (Table 4).…”

Section: Cathepsin Inhibitors and Their Therapeutic Applicationsmentioning

confidence: 99%

“…Moreover, off-target effects with broad-spectrum inhibition of proteases, leading to unpredictable side effects in clinical trials, has represented the main concern for the therapeutic use of CTS inhibitors in humans. The recent focus on target-and ligand-binding drug design to selectively inhibit specific CTSs has provided excellent results in overcoming such issue [19,72,[204][205][206][214][215][216][217][218][219][220][221][222]. In this context, several new strategies have been reported for successfully CTS targeting, including designed ankyrin repeat proteins (DARPins) with high CTSB blocking activity [222], non-peptide synthetic molecules with anti-CTSK [71] and anti-CTSD [223] activity, and naturally occurring asperphenamate [224].…”

Section: Cathepsin Inhibitors and Their Therapeutic Applicationsmentioning

confidence: 99%

“…CTSK inhibitors have been proved successful improving osteoporosis [72,73,230]; however, concerns emerged over off-target effects of the inhibitors against other CTSs and CTSK inhibition at nonbone sites (i.e., skin, and cardiovascular and cerebrovascular sites). Recently, novel selective inhibitors for CTSK have been developed, showing beneficial effects on bone and cartilage in preclinical osteoarthritis models with a safety profile [71,206].…”

Section: Cathepsin Inhibitors and Their Therapeutic Applicationsmentioning

confidence: 99%

See 1 more Smart Citation

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Pasquale

Moles

Pavone

2020

Cells

View full text Add to dashboard Cite

Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others. This review aimed to highlight the involvement of CTSs in inherited lysosomal storage disorders, with a primary focus to the emerging evidence on the role of CTSs in the pathophysiology of Mucopolysaccharidoses (MPSs). These latter diseases are characterized by severe neurological, skeletal and cardiovascular phenotypes, and no effective cure exists to date. The advance in the knowledge of the molecular mechanisms underlying the activity of CTSs in MPSs may open a new challenge for the development of novel therapeutic approaches for the cure of such intractable diseases.

show abstract

“…These structural changes are also mediated by various cellular mechanisms (e.g., local inflammation, cellular senescence, and apoptosis) involving complex cell signaling pathways (e.g., TGF-β, hedgehog, and Wnt signaling) [2][3][4] . The symptomatic benefits of existing treatments are relatively modest with significant safety concerns in some cases [5][6][7][8][9][10][11] . Currently, there are no structure-modifying agents approved for OA by the U.S. Food and Drug Administration or European Medicines Agency.…”

Section: Introductionmentioning

confidence: 99%

A Phase 2b randomized trial of lorecivivint, a novel intra-articular CLK2/DYRK1A inhibitor and Wnt pathway modulator for knee osteoarthritis

Yazıcı

McAlindon

Gibofsky

et al. 2021

Osteoarthritis and Cartilage

View full text Add to dashboard Cite

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

show abstract

Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis

Cited by 112 publications

References 36 publications

Cathepsin K: The Action in and Beyond Bone

Cathepsin K: The Action in and Beyond Bone

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

A Phase 2b randomized trial of lorecivivint, a novel intra-articular CLK2/DYRK1A inhibitor and Wnt pathway modulator for knee osteoarthritis

Contact Info

Product

Resources

About