Investigation of osteoclast cathepsin K activity in osteoclastogenesis and bone loss using a set of chemical reagents. Issue 2 (16th February 2023)

• Record Type: Journal Article
• Authors: Janiszewski, Tomasz; Kołt, Sonia; Ciastoń, Izabela; Vizovisek, Matej; Poręba, Marcin; Turk, Boris; Drąg, Marcin; Kozieł, Joanna; Kasperkiewicz, Paulina
• Is Part Of: Cell chemical biology. Volume 30:Issue 2(2023)
• Page Start: 159
• Page End: 174.e8
• Publication Date: 2023-02-16
• Subjects: osteoclast formation -- cathepsin K -- activity-based probe -- protease localization; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2023.01.001
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Cathepsin K (CatK) is a lysosomal cysteine protease whose highest expression is found in osteoclasts, which are the cells responsible for bone resorption. Investigations of the functions and physiological relevance of CatK have often relied on antibody-related techniques, which makes studying its activity patterns a challenging task. Hence, we developed a set of chemical tools for the investigation of CatK activity. We show that our probe is a valuable tool for monitoring the proteolytic activation of CatK during osteoclast formation. Moreover, we demonstrate that our inhibitor of CatK impedes osteoclastogenesis and bone resorption and that CatK is stored in its active form in osteoclasts within their lysosomal compartment and mainly in the ruffled borders of osteoclasts. Given that our probe recognizes active CatK within living cells without exhibiting any observed cytotoxicity in the several models tested, we expect that it would be well suited to theranostic applications in CatK-related diseases. Graphical abstract: Highlights: A toolbox for the investigation of osteoclast cathepsin K activity was developed Active cathepsin K is localized in the ruffled borders of osteoclasts Cathepsin K activity is associated with osteoclast formation Abstract : With a set of chemical reagents to monitor active CatK in osteoclasts, including substrate, inhibitor, and a quenched fluorescent activity-based probe, Janiszewski et al. demonstrate that active CatK is localized mainly in the ruffled borders of osteoclasts, plays a crucial role in bone loss, and is crucial in osteoclast formation.