Real-time analysis of osteoclast resorption and fusion dynamics in response to bone resorption inhibitors.

Active-site probe Bone resorption Cathepsin K Cell fusion Human osteoclast Live-imaging

Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
28 Mar 2024
Historique:
received: 18 09 2023
accepted: 19 03 2024
medline: 29 3 2024
pubmed: 29 3 2024
entrez: 29 3 2024
Statut: epublish

Résumé

Cathepsin K (CatK), an essential collagenase in osteoclasts (OCs), is a potential therapeutic target for the treatment of osteoporosis. Using live-cell imaging, we monitored the bone resorptive behaviour of OCs during dose-dependent inhibition of CatK by an ectosteric (Tanshinone IIA sulfonate) and an active site inhibitor (odanacatib). CatK inhibition caused drastic reductions in the overall resorption speed of OCs. At IC

Identifiants

pubmed: 38548807
doi: 10.1038/s41598-024-57526-9
pii: 10.1038/s41598-024-57526-9
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

7358

Subventions

Organisme : CIHR
ID : CPG-158275
Pays : Canada

Informations de copyright

© 2024. The Author(s).

Références

Raggatt, L. J. & Partridge, N. C. Cellular and molecular mechanisms of bone remodeling. J. Biol. Chem. 285, 25103–25108. https://doi.org/10.1074/jbc.R109.041087 (2010).
doi: 10.1074/jbc.R109.041087 pubmed: 20501658 pmcid: 2919071
Llorente, I., Garcia-Castaneda, N., Valero, C., Gonzalez-Alvaro, I. & Castaneda, S. Osteoporosis in rheumatoid arthritis: Dangerous liaisons. Front. Med. (Lausanne) 7, 601618. https://doi.org/10.3389/fmed.2020.601618 (2020).
doi: 10.3389/fmed.2020.601618 pubmed: 33330566
Veis, D. J. & O’Brien, C. A. Osteoclasts, master sculptors of bone. Annu. Rev. Pathol. 18, 257–281. https://doi.org/10.1146/annurev-pathmechdis-031521-040919 (2023).
doi: 10.1146/annurev-pathmechdis-031521-040919 pubmed: 36207010
Gambari, L., Grassi, F., Roseti, L., Grigolo, B. & Desando, G. Learning from monocyte-macrophage fusion and multinucleation: potential therapeutic targets for osteoporosis and rheumatoid arthritis. Int. J. Mol. Sci. 21, 6001. https://doi.org/10.3390/ijms21176001 (2020).
doi: 10.3390/ijms21176001 pubmed: 32825443 pmcid: 7504439
Kodama, J. & Kaito, T. Osteoclast multinucleation: Review of current literature. Int. J. Mol. Sci. 21, 5685. https://doi.org/10.3390/ijms21165685 (2020).
doi: 10.3390/ijms21165685 pubmed: 32784443 pmcid: 7461040
Mulari, M., Vaaraniemi, J. & Vaananen, H. K. Intracellular membrane trafficking in bone resorbing osteoclasts. Microsc. Res. Tech. 61, 496–503. https://doi.org/10.1002/jemt.10371 (2003).
doi: 10.1002/jemt.10371 pubmed: 12879417
Everts, V., Jansen, I. D. C. & de Vries, T. J. Mechanisms of bone resorption. Bone 163, 116499. https://doi.org/10.1016/j.bone.2022.116499 (2022).
doi: 10.1016/j.bone.2022.116499 pubmed: 35872106
Brömme, D. & Okamoto, K. Human cathepsin O
doi: 10.1515/bchm3.1995.376.6.379 pubmed: 7576232
Drake, F. H. et al. Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J. Biol. Chem. 271, 12511–12516 (1996).
doi: 10.1074/jbc.271.21.12511 pubmed: 8647859
Garnero, P. et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J. Biol. Chem. 273, 32347–32352 (1998).
doi: 10.1074/jbc.273.48.32347 pubmed: 9822715
Panwar, P. et al. Effects of cysteine proteases on the structural and mechanical properties of collagen fibers. J. Biol. Chem. 288, 5940–5950. https://doi.org/10.1074/jbc.M112.419689 (2013).
doi: 10.1074/jbc.M112.419689 pubmed: 23297404 pmcid: 3581366
Drake, M. T., Clarke, B. L., Oursler, M. J. & Khosla, S. Cathepsin K inhibitors for osteoporosis: Biology, potential clinical utility, and lessons learned. Endocr. Rev. https://doi.org/10.1210/er.2015-1114 (2017).
doi: 10.1210/er.2015-1114 pubmed: 28651365 pmcid: 5546879
Panwar, P. et al. A novel approach to inhibit bone resorption: Exosite inhibitors against cathepsin K. Br. J. Pharmacol. 173, 396–410. https://doi.org/10.1111/bph.13383 (2016).
doi: 10.1111/bph.13383 pubmed: 26562357
Panwar, P. et al. Tanshinones that selectively block the collagenase activity of cathepsin K provide a novel class of ectosteric antiresorptive agents for bone. Br. J. Pharmacol. 175, 902–923. https://doi.org/10.1111/bph.14133 (2018).
doi: 10.1111/bph.14133 pubmed: 29278432 pmcid: 5825304
Li, Z., Hou, W. S. & Bromme, D. Collagenolytic activity of cathepsin K is specifically modulated by cartilage-resident chondroitin sulfates. Biochemistry 39, 529–536 (2000).
doi: 10.1021/bi992251u pubmed: 10642177
Li, Z., Hou, W. S., Escalante-Torres, C. R., Gelb, B. D. & Bromme, D. Collagenase activity of cathepsin K depends on complex formation with chondroitin sulfate. J. Biol. Chem. 277, 28669–28676. https://doi.org/10.1074/jbc.M204004200 (2002).
doi: 10.1074/jbc.M204004200 pubmed: 12039963
Li, Z. et al. Regulation of collagenase activities of human cathepsins by glycosaminoglycans. J. Biol. Chem. 279, 5470–5479. https://doi.org/10.1074/jbc.M310349200 (2004).
doi: 10.1074/jbc.M310349200 pubmed: 14645229
Aguda, A. H. et al. Structural basis of collagen fiber degradation by cathepsin K. Proc. Natl. Acad. Sci. USA 111, 17474–17479. https://doi.org/10.1073/pnas.1414126111 (2014).
doi: 10.1073/pnas.1414126111 pubmed: 25422423 pmcid: 4267343
Panwar, P. et al. An ectosteric inhibitor of cathepsin K inhibits bone resorption in ovariectomized mice. J. Bone Miner. Res. 32, 2415–2430. https://doi.org/10.1002/jbmr.3227 (2017).
doi: 10.1002/jbmr.3227 pubmed: 28745432
Borggaard, X. G., Pirapaharan, D. C., Delaissé, J. M. & Søe, K. Osteoclasts’ ability to generate trenches rather than pits depends on high levels of active cathepsin K and efficient clearance of resorption products. Int. J. Mol. Sci. 21, 5924. https://doi.org/10.3390/ijms21165924 (2020).
doi: 10.3390/ijms21165924 pubmed: 32824687 pmcid: 7460581
Merrild, D. M. et al. Pit- and trench-forming osteoclasts: a distinction that matters. Bone Res. 3, 15032. https://doi.org/10.1038/boneres.2015.32 (2015).
doi: 10.1038/boneres.2015.32 pubmed: 26664853 pmcid: 4665108
Soe, K., Merrild, D. M. & Delaisse, J. M. Steering the osteoclast through the demineralization-collagenolysis balance. Bone 56, 191–198. https://doi.org/10.1016/j.bone.2013.06.007 (2013).
doi: 10.1016/j.bone.2013.06.007 pubmed: 23777960
Zhuo, Y., Gauthier, J. Y., Black, W. C., Percival, M. D. & Duong, L. T. Inhibition of bone resorption by the cathepsin K inhibitor odanacatib is fully reversible. Bone 67, 269–280. https://doi.org/10.1016/j.bone.2014.07.013 (2014).
doi: 10.1016/j.bone.2014.07.013 pubmed: 25038310
Delaisse, J. M., Søe, K., Andersen, T. L., Rojek, A. M. & Marcussen, N. The mechanism switching the osteoclast from short to long duration bone resorption. Front. Cell Dev. Biol. 9, 644503. https://doi.org/10.3389/fcell.2021.644503 (2021).
doi: 10.3389/fcell.2021.644503 pubmed: 33859985 pmcid: 8042231
Møller, A. M. J. et al. Aging and menopause reprogram osteoclast precursors for aggressive bone resorption. Bone Res. 8, 27. https://doi.org/10.1038/s41413-020-0102-7 (2020).
doi: 10.1038/s41413-020-0102-7 pubmed: 32637185 pmcid: 7329827
Soe, K. & Delaisse, J. M. Glucocorticoids maintain human osteoclasts in the active mode of their resorption cycle. J. Bone Miner. Res. 25, 2184–2192. https://doi.org/10.1002/jbmr.113 (2010).
doi: 10.1002/jbmr.113 pubmed: 20499345
Soe, K. & Delaisse, J. M. Time-lapse reveals that osteoclasts can move across the bone surface while resorbing. J. Cell Sci. 130, 2026–2035. https://doi.org/10.1242/jcs.202036 (2017).
doi: 10.1242/jcs.202036 pubmed: 28473470 pmcid: 5482982
Boissy, P., Saltel, F., Bouniol, C., Jurdic, P. & Machuca-Gayet, I. Transcriptional activity of nuclei in multinucleated osteoclasts and its modulation by calcitonin. Endocrinology 143, 1913–1921. https://doi.org/10.1210/endo.143.5.8813 (2002).
doi: 10.1210/endo.143.5.8813 pubmed: 11956174
Møller, A. M. J. et al. Fusion potential of human osteoclasts in vitro reflects age, menopause, and in vivo bone resorption levels of their donors-a possible involvement of DC-STAMP. Int. J. Mol. Sci. 21, 6368. https://doi.org/10.3390/ijms21176368 (2020).
doi: 10.3390/ijms21176368 pubmed: 32887359 pmcid: 7504560
Piper, K., Boyde, A. & Jones, S. J. The relationship between the number of nuclei of an osteoclast and its resorptive capability in vitro. Anat. Embryol. (Berl.) 186, 291–299. https://doi.org/10.1007/BF00185977 (1992).
doi: 10.1007/BF00185977 pubmed: 1416078
Møller, A. M. J. et al. Zoledronic acid is not equally potent on osteoclasts generated from different individuals. JBMR Plus 4, e10412. https://doi.org/10.1002/jbm4.10412 (2020).
doi: 10.1002/jbm4.10412 pubmed: 33210064 pmcid: 7657394
Barrow, A. D. et al. OSCAR is a collagen receptor that costimulates osteoclastogenesis in DAP12-deficient humans and mice. J. Clin. Investig. 121, 3505–3516. https://doi.org/10.1172/jci45913 (2011).
doi: 10.1172/jci45913 pubmed: 21841309 pmcid: 3163954
Boraschi-Diaz, I. et al. Collagen type I degradation fragments act through the collagen receptor LAIR-1 to provide a negative feedback for osteoclast formation. Bone 117, 23–30. https://doi.org/10.1016/j.bone.2018.09.006 (2018).
doi: 10.1016/j.bone.2018.09.006 pubmed: 30217615
Søe, K. et al. Coordination of fusion and trafficking of pre-osteoclasts at the marrow-bone interface. Calcif. Tissue Int. 105, 430–445. https://doi.org/10.1007/s00223-019-00575-4 (2019).
doi: 10.1007/s00223-019-00575-4 pubmed: 31236622
Li, B. E. et al. Visual osteoclast fusion via a fluorescence method. Sci. Rep.-Uk 8, 10184. https://doi.org/10.1038/s41598-018-28205-3 (2018).
doi: 10.1038/s41598-018-28205-3
Soe, K., Hobolt-Pedersen, A. S. & Delaisse, J. M. The elementary fusion modalities of osteoclasts. Bone 73, 181–189. https://doi.org/10.1016/j.bone.2014.12.010 (2015).
doi: 10.1016/j.bone.2014.12.010 pubmed: 25527420
Blum, G., Weimer, R. M., Edgington, L. E., Adams, W. & Bogyo, M. Comparative assessment of substrates and activity based probes as tools for non-invasive optical imaging of cysteine protease activity. Plos One 4, e6374. https://doi.org/10.1371/journal.pone.0006374 (2009).
doi: 10.1371/journal.pone.0006374 pubmed: 19636372 pmcid: 2712068
Blum, G. et al. Dynamic imaging of protease activity with fluorescently quenched activity-based probes. Nat. Chem. Biol. 1, 203–209. https://doi.org/10.1038/nchembio728 (2005).
doi: 10.1038/nchembio728 pubmed: 16408036
Everts, V. et al. Degradation of collagen in the bone-resorbing compartment underlying the osteoclast involves both cysteine-proteinases and matrix metalloproteinases. J. Cell Physiol. 150, 221–231 (1992).
doi: 10.1002/jcp.1041500202 pubmed: 1734028
Kafienah, W., Bromme, D., Buttle, D. J., Croucher, L. J. & Hollander, A. P. Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix. Biochem. J. 331, 727–732 (1998).
doi: 10.1042/bj3310727 pubmed: 9560298 pmcid: 1219411
Durdan, M. M., Azaria, R. D. & Weivoda, M. M. Novel insights into the coupling of osteoclasts and resorption to bone formation. Semin. Cell Dev. Biol. 123, 4–13. https://doi.org/10.1016/j.semcdb.2021.10.008 (2022).
doi: 10.1016/j.semcdb.2021.10.008 pubmed: 34756783
Jansen, I. D. C., Papapoulos, S. E., Bravenboer, N., de Vries, T. J. & Appelman-Dijkstra, N. M. Increased bone resorption during lactation in pycnodysostosis. Int. J. Mol. Sci. https://doi.org/10.3390/ijms22041810 (2021).
doi: 10.3390/ijms22041810 pubmed: 34360920 pmcid: 8348758
McDonald, M. M. et al. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell 184, 1940. https://doi.org/10.1016/j.cell.2021.03.010 (2021).
doi: 10.1016/j.cell.2021.03.010 pubmed: 33798441 pmcid: 8024244
Wilson, S. R., Peters, C., Saftig, P. & Bromme, D. Cathepsin K activity-dependent regulation of osteoclast actin ring formation and bone resorption. J. Biol. Chem. 284, 2584–2592 (2009).
doi: 10.1074/jbc.M805280200 pubmed: 19028686 pmcid: 2629117
Taira, T. M. et al. HBP/O-GlcNAcylation metabolic axis regulates bone resorption outcome. J. Dent Res. 102, 440–449. https://doi.org/10.1177/00220345221141043 (2023).
doi: 10.1177/00220345221141043 pubmed: 36749069
Takito, J., Inoue, S. & Nakamura, M. The sealing zone in osteoclasts: A self-organized structure on the bone. Int. J. Mol. Sci. https://doi.org/10.3390/ijms19040984 (2018).
doi: 10.3390/ijms19040984 pubmed: 29587415 pmcid: 5979552
Kong, L. et al. Integrin-associated molecules and signalling cross talking in osteoclast cytoskeleton regulation. J. Cell Mol. Med. 24, 3271–3281. https://doi.org/10.1111/jcmm.15052 (2020).
doi: 10.1111/jcmm.15052 pubmed: 32045092 pmcid: 7131929
Leung, P., Pickarski, M., Zhuo, Y., Masarachia, P. J. & Duong, L. T. The effects of the cathepsin K inhibitor odanacatib on osteoclastic bone resorption and vesicular trafficking. Bone 49, 623–635. https://doi.org/10.1016/j.bone.2011.06.014 (2011).
doi: 10.1016/j.bone.2011.06.014 pubmed: 21718816
Jobke, B., Milovanovic, P., Amling, M. & Busse, B. Bisphosphonate-osteoclasts: Changes in osteoclast morphology and function induced by antiresorptive nitrogen-containing bisphosphonate treatment in osteoporosis patients. Bone 59, 37–43. https://doi.org/10.1016/j.bone.2013.10.024 (2014).
doi: 10.1016/j.bone.2013.10.024 pubmed: 24211427
Leger, B. et al. Inadequate response to treatment reveals persistent osteoclast bone resorption in osteoporotic patients. Bone 153, 116167. https://doi.org/10.1016/j.bone.2021.116167 (2021).
doi: 10.1016/j.bone.2021.116167 pubmed: 34492359
Weinstein, R. S., Roberson, P. K. & Manolagas, S. C. Giant osteoclast formation and long-term oral bisphosphonate therapy. N. Engl. J. Med. 360, 53–62 (2009).
doi: 10.1056/NEJMoa0802633 pubmed: 19118304 pmcid: 2866022
Pirapaharan, D. C. et al. Catabolic activity of osteoblast lineage cells contributes to osteoclastic bone resorption in vitro. J. Cell Sci. https://doi.org/10.1242/jcs.229351 (2019).
doi: 10.1242/jcs.229351 pubmed: 30975918
Runger, T. M. et al. Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib. J. Am. Acad. Dermatol. 66, e89-96. https://doi.org/10.1016/j.jaad.2010.11.033 (2012).
doi: 10.1016/j.jaad.2010.11.033 pubmed: 21571394
McClung, M. R. et al. Odanacatib for the treatment of postmenopausal osteoporosis: results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT Extension study. Lancet Diabetes Endocrinol. 7, 899–911. https://doi.org/10.1016/S2213-8587(19)30346-8 (2019).
doi: 10.1016/S2213-8587(19)30346-8 pubmed: 31676222
Møller, A. M., Delaissé, J. M. & Søe, K. Osteoclast fusion: Time-lapse reveals involvement of CD47 and syncytin-1 at different stages of nuclearity. J. Cell Physiol. 232, 1396–1403. https://doi.org/10.1002/jcp.25633 (2017).
doi: 10.1002/jcp.25633 pubmed: 27714815

Auteurs

Preety Panwar (P)

Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada.
Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
Department of Pharmaceutical Sciences, Elizabeth City State University, Elizabeth City, NC, USA.

Jacob Bastholm Olesen (JB)

Clinical Cell Biology, Pathology Research Unit, Department of Clinical Research, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark.
Department of Pathology, Odense University Hospital, Odense, Denmark.

Galia Blum (G)

Faculty of Medicine, Campus Ein Karem, The School of Pharmacy, Institute of Drug Research, The Hebrew University of Jerusalem, Room 407, 9112001, Jerusalem, Israel.

Jean-Marie Delaisse (JM)

Clinical Cell Biology, Pathology Research Unit, Department of Clinical Research, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark.

Kent Søe (K)

Clinical Cell Biology, Pathology Research Unit, Department of Clinical Research, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark. kent.soee@rsyd.dk.
Department of Pathology, Odense University Hospital, Odense, Denmark. kent.soee@rsyd.dk.
Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark. kent.soee@rsyd.dk.

Dieter Brömme (D)

Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada. dbromme@dentistry.ubc.ca.
Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. dbromme@dentistry.ubc.ca.

Classifications MeSH