Affinage

CTSK

Cathepsin K · UniProt P43235

Round 2 corrected
Length
329 aa
Mass
37.0 kDa
Annotated
2026-04-28
101 papers in source corpus 39 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Cathepsin K is a lysosomal cysteine protease of the papain superfamily that serves as the principal collagenase in osteoclast-mediated bone resorption and a key regulator of extracellular matrix turnover in multiple tissues. Its unique collagenolytic activity requires oligomerization with chondroitin sulfate glycosaminoglycans into a pentameric complex (5:5 stoichiometry), in which C-shaped dimers bridged by GAGs bind collagen fibrils at the gap region and unfold triple-helical collagen via residues Q21 and Q92; monomeric cathepsin K retains only gelatinase activity (PMID:12039963, PMID:25422423, PMID:14645229). Loss-of-function mutations in CTSK cause pycnodysostosis, an autosomal recessive osteosclerosis, by abolishing osteoclastic collagen degradation (PMID:8703060). CTSK transcription during osteoclastogenesis is cooperatively driven by RANKL-induced p38/NFATc1 signaling in concert with PU.1 and MITF, and by an Sgk1–Stat3–Mycl axis, while beyond bone CTSK maintains ECM homeostasis in lung and synovial fibroblasts and mediates lysosomal degradation of CXCL1 in tumor-associated macrophages to modulate angiogenesis (PMID:15304486, PMID:41266497, PMID:15161653, PMID:11733367, PMID:41072283).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1995 High

    Molecular cloning of cathepsin K established it as a novel papain-family cysteine proteinase with predominant osteoclast expression, answering the question of which protease mediates osteoclastic bone matrix degradation.

    Evidence cDNA library screening with rabbit OC-2 probe, Northern blot tissue distribution in human tissues and osteoclastomas

    PMID:7576232 PMID:7805878 PMID:7818555

    Open questions at the time
    • Substrate specificity not yet defined
    • No in vivo loss-of-function evidence
    • Mechanism of activation unknown
  2. 1996 High

    Identification of CTSK mutations as the cause of pycnodysostosis, combined with in vitro demonstration of collagenolytic and osteonectin-degrading activity, linked cathepsin K enzymatic function directly to human skeletal disease and defined its key substrates.

    Evidence Genetic linkage and Sanger sequencing in pycnodysostosis families; baculovirus-expressed recombinant cathepsin K tested on type I collagen, osteonectin, and fluorogenic peptides with inhibitor profiling

    PMID:8647860 PMID:8703060

    Open questions at the time
    • Mechanism of collagen triple-helix cleavage unknown
    • No crystal structure yet
    • Quantitative genotype–phenotype relationship not established
  3. 1997 High

    The crystal structure of cathepsin K complexed with an inhibitor revealed the active-site architecture, and immunolocalization placed cathepsin K at the osteoclast ruffled border during active resorption, linking structural knowledge to the subcellular site of bone degradation.

    Evidence X-ray crystallography of inhibitor-bound cathepsin K; immunohistochemistry and in situ hybridization on bone and giant cell tumor sections

    PMID:9028530 PMID:9033587

    Open questions at the time
    • How cathepsin K achieves collagenase versus gelatinase selectivity is unknown
    • No information on cofactor requirements
    • Genomic regulation largely unexplored
  4. 1998 High

    Discovery that the serpin SCCA1 forms a stable 1:1 inhibitory complex with cathepsin K with rapid kinetics identified the first endogenous cross-class inhibitor, establishing a regulatory mechanism for controlling cathepsin K activity.

    Evidence Kinetic analysis with second-order rate constants, stoichiometry measurement, SDS-PAGE detection of stable complex

    PMID:9548757

    Open questions at the time
    • Physiological relevance of SCCA1 inhibition in bone or other tissues not shown
    • Other endogenous inhibitors not surveyed
    • In vivo consequence of disrupting this interaction unknown
  5. 2002 High

    The requirement for chondroitin sulfate GAG complex formation (5:5 oligomer) for collagenase activity, versus monomeric gelatinase activity, resolved why the Y212C pycnodysostosis mutant retains gelatinase but not collagenase function, fundamentally distinguishing cathepsin K from other cysteine cathepsins.

    Evidence In vitro complex formation, collagen and gelatin degradation assays, analysis of Y212C pycnodysostosis mutant

    PMID:12039963 PMID:14645229

    Open questions at the time
    • Structural basis of the oligomeric complex not yet visualized
    • Identity of GAG-binding residues not mapped
    • Whether other GAGs serve as cofactors in non-bone tissues unknown
  6. 2004 High

    RANKL-induced transcriptional regulation of CTSK was dissected: p38 MAPK phosphorylates NFATc1, which complexes with PU.1 and MITF at the CTSK promoter, explaining how osteoclast differentiation signals converge to activate this effector protease gene.

    Evidence Cathepsin K promoter deletion reporter assays, overexpression in RAW264 cells, p38 inhibitor SB203580, nuclear localization studies

    PMID:15304486

    Open questions at the time
    • Chromatin accessibility and epigenetic regulation at the CTSK locus not examined
    • Relative contribution of each transcription factor not quantified
    • Whether this promoter logic applies in non-osteoclast cell types is unknown
  7. 2004 High

    Demonstration that CTSK-knockout mice develop exacerbated lung fibrosis after bleomycin challenge, with reduced fibroblast collagenolytic activity, established cathepsin K as a homeostatic protease in extracellular matrix turnover beyond bone.

    Evidence Bleomycin-induced fibrosis in Ctsk−/− mice, primary lung fibroblast collagenolytic assays

    PMID:15161653

    Open questions at the time
    • Whether cathepsin K acts intracellularly or extracellularly in lung fibroblasts unclear
    • Specific collagen substrates in lung not identified
    • Compensation by other cathepsins not assessed
  8. 2014 High

    Structural resolution of the collagenolytically active cathepsin K dimer bridged by GAGs, with mutagenesis proving that Q21 and Q92 mediate collagen unfolding while the dimer interface is essential for fibrillar degradation, provided a complete structural mechanism for collagenolysis distinct from MMP-type collagenases.

    Evidence Crystal structure of cathepsin K dimer, site-directed mutagenesis of Q21/Q92 and dimer interface, SEM of collagen fiber binding, Edman degradation of cleavage sites

    PMID:25422423

    Open questions at the time
    • Full atomic model of the cathepsin K–GAG–collagen ternary complex not available
    • Dynamics of dimer assembly on the collagen fiber in vivo unknown
    • Whether the dimer mechanism applies to non-type-I collagens not tested
  9. 2012 High

    Ctsk-knockout mice showed delayed osteoarthritis progression with reduced MMP-13 and ADAMTS-5 expression, revealing that cathepsin K not only directly degrades cartilage matrix but also cross-regulates other cartilage-degrading proteases, amplifying joint destruction.

    Evidence Ctsk−/− mouse DMM OA model, histologic scoring, IHC for MMP-13/ADAMTS-5

    PMID:21968827

    Open questions at the time
    • Whether cathepsin K regulates MMP-13/ADAMTS-5 transcriptionally or post-translationally unknown
    • Human OA validation lacking
    • Relative contribution of osteoclasts versus chondrocytes not resolved
  10. 2025 Medium

    An Sgk1–Stat3–Mycl transcriptional axis was identified as a parallel pathway to NFATc1 for driving CTSK expression during osteoclastogenesis, with Mycl directly binding the CTSK promoter and rescuing differentiation impaired by Sgk1 inhibition.

    Evidence Sgk1 inhibitor (GSK650394), Mycl overexpression rescue, Ctsk promoter binding assay, in vivo micro-CT

    PMID:41266497

    Open questions at the time
    • Relative contribution of Mycl versus NFATc1 at the endogenous CTSK promoter not quantified
    • ChIP-seq confirmation of Mycl occupancy lacking
    • Single lab with single inhibitor
  11. 2025 Medium

    Cathepsin K was shown to mediate lysosomal degradation of CXCL1 in tumor-associated macrophages, suppressing CXCL1-driven neoangiogenesis, extending cathepsin K's functional roles into immune–tumor microenvironment regulation.

    Evidence CXCL1–lysosome colocalization, CTSK expression modulation, breast cancer xenograft and zebrafish angiogenesis models

    PMID:41072283

    Open questions at the time
    • Whether CXCL1 is a direct cathepsin K substrate or degraded via secondary lysosomal proteases not distinguished
    • Generalizability to other tumor types untested
    • Single study

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of the cathepsin K–GAG–collagen ternary complex, the in vivo relevance of SCCA1 inhibition, the mechanistic basis for cathepsin K's regulation of downstream proteases (MMP-13, ADAMTS-5), and the full scope of cathepsin K substrates and functions in non-bone tissues such as the tumor microenvironment.
  • No ternary complex structure
  • SCCA1 inhibition not validated in vivo
  • Substrate repertoire beyond collagen I and aggrecan incompletely catalogued

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0140096 catalytic activity, acting on a protein 5
Localization
GO:0005576 extracellular region 3 GO:0005764 lysosome 3
Pathway
R-HSA-1474244 Extracellular matrix organization 6 R-HSA-1643685 Disease 5 R-HSA-392499 Metabolism of proteins 4
Partners
MITFMYCLNFATC1PU.1SCCA1TFEB
Complex memberships
Cathepsin K–chondroitin sulfate pentameric complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Pycnodysostosis (autosomal recessive osteosclerosis) is caused by loss-of-function mutations in cathepsin K (CTSK), establishing that CTSK is a lysosomal cysteine protease essential for osteoclast-mediated bone resorption; nonsense, missense, and stop-codon mutations were identified in affected patients. Genetic linkage mapping, Sanger sequencing of patient DNA, transient expression of mutant cDNA with Western blot to confirm absence of protein Science High 8703060
1995 Human cathepsin K was molecularly cloned and identified as a novel cysteine proteinase of the papain superfamily, predominantly expressed in osteoclasts and osteoclastomas, implicating it as the major protease in osteoclastic bone resorption. cDNA library screening using rabbit OC-2 probe, Northern blot analysis of tissue distribution Biochemical and biophysical research communications High 7576232 7805878 7818555
1996 Recombinant cathepsin K is a cysteine protease that degrades type I collagen and osteonectin (bone matrix proteins) in vitro; it is activated upon removal of its inhibitory pro-sequence, is inhibited by E-64 and leupeptin but not by pepstatin or EDTA, and cleaves fluorogenic peptide substrates. Baculovirus expression, purification, in vitro enzyme activity assays with fluorogenic peptides, collagen degradation assay, inhibitor profiling The Journal of biological chemistry High 8647860
1997 Crystal structure of human cathepsin K complexed with a potent inhibitor was determined, revealing the active-site architecture of this papain-family cysteine protease. X-ray crystallography Nature structural biology High 9033587
1997 CTSK gene was mapped to chromosome 1q21 by fluorescence in situ hybridization; genomic organization established as 8 exons/7 introns spanning ~12.1 kb; a single transcription start site 49 bp upstream of the initiator Met was identified; the 5' flanking region lacks canonical TATA/CAAT boxes, suggesting non-canonical transcriptional regulation. FISH, PCR on genomic DNA, P1 clone isolation, ribonuclease protection assay, 5' RACE Genomics High 9143491
1997 Cathepsin K protein is specifically localized to osteoclasts within bone tissue; in actively resorbing osteoclasts, immunostaining localizes cathepsin K at the ruffled border, and in giant cell tumors it is found in lysosomal vacuoles that fuse with the cell membrane. In situ hybridization and immunohistochemistry on bone and giant cell tumor sections Bone High 9028530
1998 SCCA1 (squamous cell carcinoma antigen 1), a serpin, is a potent cross-class inhibitor of cathepsin K, acting with 1:1 stoichiometry and second-order rate constants ≥1×10⁵ M⁻¹s⁻¹, forming stable complexes via a mechanism similar to serpin-serine protease interactions involving cleavage at the reactive site loop. Kinetic analysis (second-order rate constants, stoichiometry, complex stability), SDS-PAGE to detect stable inhibitor-protease complex Biochemistry High 9548757
1999 Complete mouse Ctsk gene was characterized (8 exons, 7 introns, ~10.1 kb), showing conserved exon sizes with the human gene; Ctsk is located ~4.5 kb downstream of the Arnt gene on mouse chromosome 3. Genomic cloning, sequence analysis, chromosomal mapping Matrix biology Medium 10372556
1999 CTSK mutations that reduce cathepsin K protein to virtually absent levels cause pycnodysostosis, while ~50-80% reduced protein levels (in heterozygous parents) have no phenotypic effect, establishing a threshold for cathepsin K in bone resorption. DNA sequencing of patient/family members, Western blot for protein expression levels Journal of bone and mineral research High 10491211
2000 Recombinant human cathepsin K cleaves the trivalently cross-linked ICTP (carboxyterminal telopeptide of type I collagen) at two sites between the phenylalanine-rich region and the cross-link, destroying ICTP immunoreactivity; MMP-9, MMP-1, and MMP-13 do not have this effect, distinguishing cathepsin K-mediated from MMP-mediated collagen degradation in bone. In vitro proteolytic cleavage assay with recombinant cathepsin K and MMPs, immunochemical detection of ICTP degradation products Bone High 10719280
2001 Cathepsin K is expressed in synovial fibroblasts (SFs) in rheumatoid arthritis and is the critical protease for SF-mediated intralysosomal collagen degradation; co-culture of SFs on cartilage showed collagen fibril phagocytosis and lysosomal hydrolysis blocked by cathepsin K inhibitor but not by inhibitors of cathepsins L, B, and S. Cathepsin K also has potent aggrecan-degrading activity, and cathepsin K-generated aggrecan fragments potentiate its own collagenolytic activity. Immunostaining of RA joint specimens, primary SF cell culture, co-culture on cartilage disks, selective protease inhibitors, collagen degradation assay The American journal of pathology High 11733367
2002 Cathepsin K collagenase activity requires complex formation with chondroitin sulfate glycosaminoglycans; the active complex is an oligomer of five cathepsin K and five chondroitin sulfate molecules. Monomeric cathepsin K has no collagenase activity but retains gelatinase activity. The Y212C pycnodysostosis-causing mutant cannot form these complexes and therefore lacks collagenase activity despite retaining gelatinase activity. In vitro complex formation assay, collagen and gelatin degradation assays, analysis of pycnodysostosis mutant Y212C The Journal of biological chemistry High 12039963
2003 Chondroitin sulfate and keratan sulfate (GAGs predominant in bone and cartilage) enhance cathepsin K's collagenolytic activity, while dermatan sulfate, heparan sulfate, and heparin selectively inhibit it. Complex formation with GAGs is unique to cathepsin K among papain-like cysteine proteases; cathepsins L and S do not form these complexes and their collagenase activity is inhibited by GAGs at 37°C. In vitro collagen degradation assays with different GAGs, comparative analysis across cathepsin family members The Journal of biological chemistry High 14645229
2004 p38 MAP kinase is required for maximal RANKL-induced cathepsin K gene expression during osteoclastogenesis; RANKL-induced NFATc1 is phosphorylated by activated p38 MAP kinase, then forms a complex with PU.1 in osteoclast nuclei; NFATc1, PU.1, and MITF synergistically enhance cathepsin K promoter activity. Reporter gene assay with cathepsin K 5'-deletion constructs, overexpression in RAW264 cells, p38-specific inhibitor (SB203580), nuclear localization studies The Journal of biological chemistry High 15304486
2004 Cathepsin K plays a pivotal role in lung matrix homeostasis; CTSK-/- mice develop significantly more extracellular matrix deposition and fibrosis after bleomycin challenge. Primary lung fibroblasts from CTSK-/- mice show decreased collagenolytic activity, and human pulmonary fibroblasts upregulate cathepsin K activity during activation. Bleomycin-induced fibrosis model in Ctsk knockout mice, primary fibroblast collagenolytic activity assays, gene expression analysis The American journal of pathology High 15161653
2005 ARNT transcripts read through the ARNT-CTSK intergenic region and extend into CTSK intron 3 (~3.7 kb downstream of the longest known ARNT mRNA); this may negatively impact CTSK transcript levels by interfering with CTSK expression. Novel CTSK transcripts with alternate 5' splicing and a cryptic upstream promoter were also identified. RT-PCR spanning ARNT-CTSK intergenic region, quantitative RT-PCR from multiple tissues, EST sequence analysis Comparative and functional genomics Medium 18629217
2007 Nine novel CTSK mutations causing pycnodysostosis were characterized; the L7P mutation in the signal peptide significantly reduces protein expression, indicating the signal peptide is required for targeting and translocation of cathepsin K across the ER membrane. Other missense mutations were predicted by 3D structural modeling to cause incorrect protein folding. Sanger sequencing, Western blot of COS-7 cells transfected with mutant CTSK cDNAs, 3D structural modeling Human mutation Medium 17397052
2009 Cathepsin K is expressed by translocation renal cell carcinomas bearing TFE3 or TFEB translocations; overexpression of TFEB (or related TFE family members including MITF) drives cathepsin K expression, identifying CTSK as a transcriptional target of the MiTF/TFE transcription factor family. Immunohistochemistry of cytogenetically confirmed translocation RCCs and control renal neoplasms (n=210+ cases) Modern pathology Medium 19396149
2012 Ctsk knockout mice show delayed osteoarthritic progression in a joint destabilization model; CTK-positive chondrocytes and synovial cells are identified as sources of cathepsin K driving OA, and loss of cathepsin K reduces expression of MMP-13 and ADAMTS-5 in chondrocytes. Ctsk-/- mouse model, destabilization of medial meniscus surgery, histologic scoring (modified Mankin), immunohistochemistry for CTK, MMP-13, ADAMTS-5, TRAP Arthritis and rheumatism High 21968827
2014 Structural basis for cathepsin K collagen fiber degradation was established: cathepsin K forms elongated C-shaped protein dimers that constitute the collagenolytically active unit; glycosaminoglycans bridge the dimer and provide a putative collagen-binding interface. Residues Q21 and Q92 (outside the active site) participate in collagen unfolding; mutations at these sites or perturbation of the dimer interface abolish fiber degradation without affecting gelatin or peptide hydrolysis. Cathepsin K binds specifically at the fibrillar gap region of collagen fibers. Crystal structure of cathepsin K dimer, molecular modeling of collagen binding, site-directed mutagenesis of Q21/Q92 and dimer interface, scanning electron microscopy of fiber binding, Edman degradation to identify cleavage sites Proceedings of the National Academy of Sciences of the United States of America High 25422423
2015 Novel compound heterozygous CTSK mutations (p.W29X and p.Y283C) cause pycnodysostosis with dental abnormalities including thickened, softened cementum; the Y283C mutation does not affect mRNA or protein levels but significantly reduces CTSK enzyme activity, and structural modeling shows Y283C disrupts the hydrogen network affecting enzyme self-cleavage/activation. Histology, atomic force microscopy, micro-CT, in vitro enzyme activity assay in COS-7 cells overexpressing mutant CTSK, 3D structural modeling Journal of dental research Medium 25731711
2018 Ctsk-/- mice show delayed OA progression with reduced chondroclast numbers in the growth plate relative to WT; differential gene expression in laser-captured osteoclasts and chondroclasts from Ctsk-/- mice revealed altered expression of Atp6v0d2, Tnfrsf11a, Ca2, Calcr, Ccr1, Gpr68, Itgb3, Nfatc1, and Syk, suggesting cathepsin K differentially regulates chondroclastogenesis. Ctsk-/- mouse model, DMM surgery, laser capture microdissection, targeted PCR arrays, histomorphometry Journal of cellular physiology Medium 29781506
2019 Cathepsin K (Ctsk) regulates TLR9 signaling and autophagy in the context of periodontitis with rheumatoid arthritis; inhibition of Ctsk in vivo (via AAV or BML-244) reduces TLR9, TFEB, LC3, macrophage infiltration, and inflammatory cytokines in periodontal lesions; in vitro, Ctsk inhibition specifically suppresses TLR9-downstream signaling proteins and autophagy-related proteins in macrophages. DBA/J1 mouse model, AAV-mediated Ctsk knockdown, BML-244 inhibitor, Western blot, IHC, qRT-PCR, IF, siRNA in macrophages, CpG ODN stimulation Cell proliferation / Journal of clinical periodontology Medium 30636333 31737959
2020 RUNX2 promotes osteoclast differentiation and bone resorption through the AKT/NFATc1/CTSK axis: wild-type RUNX2 increases mTORC2 activity and specifically promotes AKT phosphorylation at Ser473, which enhances NFATc1 nuclear translocation and increases CTSK expression; AKT inhibition abolishes this, and constitutively active AKT rescues osteoclastogenesis in mutant cells. Stable RAW264.7 cell lines expressing WT or mutant RUNX2, F-actin ring formation assay, bone resorption pit assay, mTORC2/AKT inhibition, NFATc1 nuclear translocation assay, Western blot Calcified tissue international Medium 32008052
2022 CTSK mediates castration-resistant prostate cancer (CRPC) growth and metastasis via the IL-17 signaling/CTSK/EMT axis; CTSK promotes EMT to drive metastasis and proliferation, and CTSK expression is linked to M2 macrophage polarization, forming a feedback circuit between M2 TAMs and CRPC tissue. In vivo and in vitro experiments in CRPC cells, gene knockdown/overexpression, IL-17 pathway manipulation, M2 macrophage co-culture, EMT marker analysis Cell death & disease Medium 36138018
2022 Loss of Trp53 and Rb1 in Ctsk-expressing cells drives osteosarcoma via YAP activation; YAP/TEAD1 complex binds the Glut1 promoter to upregulate glucose transporter expression, leading to overactive glucose metabolism; ablation of YAP signaling inhibits energy metabolism and delays osteosarcoma progression in Ctsk-Cre;Trp53f/f/Rb1f/f mice. Conditional KO mouse model (Ctsk-Cre;Trp53f/f/Rb1f/f), mechanistic studies of YAP expression/activity, promoter luciferase for Glut1, YAP inhibition MedComm Medium 35615117
2023 Sfrp4 is required for maintenance of Ctsk-lineage periosteal stem cells (PSCs); Sfrp4 deletion reduces the PSC pool, impairs clonal multipotency for osteoblast/chondrocyte differentiation, and abolishes the PTH-dependent increase in PSC numbers and cortical bone formation; Sfrp4 regulates Ctsk-lineage PSCs by maintaining Wnt signaling and Hh pathway-associated genes. Sfrp4 global deletion mouse model, Ctsk-lineage tracing, clonal multipotency assays, bulk RNA sequencing of Ctsk-lineage PSCs, PTH treatment, periosteal injury model Proceedings of the National Academy of Sciences of the United States of America Medium 37931101
2024 METTL3-mediated m6A modification regulates Ctsk expression in calvarial Ctsk+ stem cells; loss of Mettl3 in Ctsk+ lineage cells reduces Hedgehog (Hh) signaling, delays suture formation, and impairs calvarial bone formation; restoration of Hh signaling partially rescues these defects. Conditional Mettl3 KO in Ctsk-Cre mice, MeRIP-seq plus RNA-seq, micro-CT, histology, Sufu allele crossing for Hh restoration, SAG21 local administration Journal of dental research Medium 38752256
2024 T-2 toxin induces cartilage ECM degradation by downregulating METTL3-mediated m6A methylation of Ctsk mRNA; METTL3 silencing exacerbates HT-2 toxin-induced ECM degradation, while Ctsk silencing also aggravates it, suggesting Ctsk normally has a protective role in cartilage maintenance; dietary methionine supplementation increases m6A levels in vivo and mitigates cartilage damage. MeRIP-seq, RNA-seq, siRNA knockdown of METTL3 and Ctsk in chondrocytes, in vivo methionine supplementation International immunopharmacology Medium 39426235
2025 Loss of CTSK in trabecular meshwork (TM) cells disrupts collagen biogenesis and ECM homeostasis; siRNA knockdown of CTSK increases intracellular calcium, activates PRKD1 which drives LIMK1/SSH1/cofilin-mediated actin polymerization and focal adhesion maturation, and downregulates RhoQ and myosin motor proteins, indicating altered mechanotransduction; apoptotic markers increase without caspase 3/7 activation, suggesting apoptosis-independent remodeling. siRNA-mediated CTSK knockdown in human TM cells, unbiased proteomics (mass spectrometry), intracellular calcium measurement, actin/focal adhesion imaging bioRxiv (preprint)preprint Medium bio_10.1101_2025.02.10.637394
2025 HIF-1α in Ctsk+ osteoclasts regulates lysosomal biogenesis via the TSC2-mTORC1-TFEB axis; conditional HIF-1α knockout in Ctsk+ cells causes disorganized ruffled borders, defective lysosomal biogenesis, and abnormal condylar morphogenesis with calcified cartilage accumulation and impaired subchondral bone formation. DTR transgenic and conditional HIF-1α knockout (HIF-1α∆ctsk-cre) mouse models, histology, micro-CT, cellular ultrastructure analysis, gene expression Journal of dental research Medium 41108121
2025 Sgk1 regulates osteoclastogenesis via Stat3 phosphorylation at Tyr705, leading to Mycl upregulation; Mycl directly binds the Ctsk promoter and drives Ctsk transcription; Mycl overexpression rescues osteoclast differentiation impaired by Sgk1 inhibition, defining a Sgk1-Stat3-Mycl-Ctsk signaling axis. Sgk1 inhibitor (GSK650394), Mycl overexpression rescue in osteoclasts, Ctsk promoter binding assay, in vivo micro-CT in Sgk1 inhibitor-treated mice Scientific reports Medium 41266497
2025 Tucatinib directly binds and inhibits CTSK enzymatic activity (confirmed by microscale thermophoresis and CTSK activity assays); it also suppresses NFATc1-driven osteoclast differentiation by inhibiting DRP1 phosphorylation at Ser616, reducing mitochondrial ROS and stabilizing mitochondrial dynamics, thereby defining a DRP1/NFATc1/CTSK axis in osteoclastogenesis. Virtual screening, microscale thermophoresis, CTSK activity assays, DRP1 phosphorylation assay, mtROS measurement, ovariectomized mouse model Biochemical pharmacology Medium 41974330
2025 Liquiritin enhances CTSK-mediated lysosomal degradation of CXCL1 in tumor-associated macrophages (TAMs); liquiritin accumulates in TAM lysosomes, increases CXCL1 and lysosome colocalization, and upregulates CTSK expression to accelerate CXCL1 degradation, thereby suppressing CXCL1-driven breast cancer neoangiogenesis. TAM membrane-capture/LC-MS screening, CXCL1 ELISA, lysosome/CXCL1 colocalization assay, CTSK expression measurement, in vivo breast cancer xenograft and zebrafish models Phytomedicine Medium 41072283
2013 Caffeine directly enhances osteoclast differentiation and maturation by activating p38 MAP kinase, which induces Mitf expression and transcriptional upregulation of DC-STAMP (cell fusion), and ultimately increases cathepsin K (CtsK) and TRAP expression; the p38 inhibitor SB203580 blocks caffeine-induced CtsK upregulation. TRAP staining of osteoclasts, p38 inhibitor, real-time PCR, luciferase reporter for DC-STAMP Cellular signalling Medium 23434822
2003 Cathepsin K is expressed by prostate cancer cells and is enzymatically active (collagenase and fluorogenic peptide activity); cathepsin K mRNA and protein are present in prostate cancer cell lines and primary tumors, with significantly higher expression in bone metastases than primary cancer, and serum NTx (a cathepsin K-mediated bone resorption marker) is elevated in patients with bone metastases. RT-PCR, in situ hybridization, immunohistochemistry, Western blot after immunoprecipitation, fluorogenic enzyme activity assay, type I collagen degradation assay Journal of bone and mineral research Medium 12568399

Source papers

Stage 0 corpus · 101 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2003 Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science (New York, N.Y.) 1117 14684825
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1996 Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science (New York, N.Y.) 779 8703060
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. The Journal of biological chemistry 409 8647860
2004 Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1. The Journal of biological chemistry 351 15304486
1995 Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone. Biochemical and biophysical research communications 291 7818555
1998 Cross-class inhibition of the cysteine proteinases cathepsins K, L, and S by the serpin squamous cell carcinoma antigen 1: a kinetic analysis. Biochemistry 242 9548757
1995 Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution. Biological chemistry Hoppe-Seyler 224 7576232
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2003 Regulation of collagenase activities of human cathepsins by glycosaminoglycans. The Journal of biological chemistry 185 14645229
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2004 Pivotal role of cathepsin K in lung fibrosis. The American journal of pathology 163 15161653
1995 Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit OC2. FEBS letters 163 7805878
1997 Localization of cathepsin K in human osteoclasts by in situ hybridization and immunohistochemistry. Bone 162 9028530
2001 Cathepsin k is a critical protease in synovial fibroblast-mediated collagen degradation. The American journal of pathology 148 11733367
2009 Cathepsin-K immunoreactivity distinguishes MiTF/TFE family renal translocation carcinomas from other renal carcinomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 146 19396149
2002 Collagenase activity of cathepsin K depends on complex formation with chondroitin sulfate. The Journal of biological chemistry 144 12039963
1997 Crystal structure of human cathepsin K complexed with a potent inhibitor. Nature structural biology 138 9033587
2007 An intracellular serpin regulates necrosis by inhibiting the induction and sequelae of lysosomal injury. Cell 133 17889653
2000 Immunochemical characterization of assay for carboxyterminal telopeptide of human type I collagen: loss of antigenicity by treatment with cathepsin K. Bone 132 10719280
2003 Cathepsin K mRNA and protein expression in prostate cancer progression. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 131 12568399
2011 Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3. Nature genetics 123 21983785
2014 Structural basis of collagen fiber degradation by cathepsin K. Proceedings of the National Academy of Sciences of the United States of America 121 25422423
2005 Mycobacterium tuberculosis serine/threonine kinases PknB, PknD, PknE, and PknF phosphorylate multiple FHA domains. Protein science : a publication of the Protein Society 70 15987910
2022 Cathepsin K regulates the tumor growth and metastasis by IL-17/CTSK/EMT axis and mediates M2 macrophage polarization in castration-resistant prostate cancer. Cell death & disease 65 36138018
2012 Role of Mycobacterium tuberculosis pknD in the pathogenesis of central nervous system tuberculosis. BMC microbiology 60 22243650
2006 Mycobacterium tuberculosis transporter MmpL7 is a potential substrate for kinase PknD. Biochemical and biophysical research communications 57 16879801
2007 Molecular analysis and characterization of nine novel CTSK mutations in twelve patients affected by pycnodysostosis. Mutation in brief #961. Online. Human mutation 54 17397052
2004 Sensor domain of the Mycobacterium tuberculosis receptor Ser/Thr protein kinase, PknD, forms a highly symmetric beta propeller. Journal of molecular biology 53 15136047
2013 Caffeine enhances osteoclast differentiation and maturation through p38 MAP kinase/Mitf and DC-STAMP/CtsK and TRAP pathway. Cellular signalling 48 23434822
2012 Osteoarthritic change is delayed in a Ctsk-knockout mouse model of osteoarthritis. Arthritis and rheumatism 47 21968827
2007 Allosteric activation by dimerization of the PknD receptor Ser/Thr protein kinase from Mycobacterium tuberculosis. The Journal of biological chemistry 44 17242402
2019 Inhibition of Ctsk modulates periodontitis with arthritis via downregulation of TLR9 and autophagy. Cell proliferation 42 31737959
1999 Mutations of CTSK result in pycnodysostosis via a reduction in cathepsin K protein. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 41 10491211
1997 Genomic organization and chromosome localization of the human cathepsin K gene (CTSK). Genomics 38 9143491
2019 Inhibition of Ctsk alleviates periodontitis and comorbid rheumatoid arthritis via downregulation of the TLR9 signalling pathway. Journal of clinical periodontology 34 30636333
2007 Chlamydophila pneumoniae PknD exhibits dual amino acid specificity and phosphorylates Cpn0712, a putative type III secretion YscD homolog. Journal of bacteriology 33 17766419
1998 Cloning and characterisation of the pknD gene encoding an eukaryotic-type protein kinase in the cyanobacterium Anabaena sp. PCC7120. Molecular & general genetics : MGG 33 9613569
2020 New Function of RUNX2 in Regulating Osteoclast Differentiation via the AKT/NFATc1/CTSK Axis. Calcified tissue international 31 32008052
2018 LncRNA-Jak3:Jak3 coexpressed pattern regulates monosodium urate crystal-induced osteoclast differentiation through Nfatc1/Ctsk expression. Environmental toxicology 27 30387921
2015 Dental Abnormalities Caused by Novel Compound Heterozygous CTSK Mutations. Journal of dental research 26 25731711
2017 SNPs near the cysteine proteinase cathepsin O gene (CTSO) determine tamoxifen sensitivity in ERα-positive breast cancer through regulation of BRCA1. PLoS genetics 25 28968398
2013 Exome sequencing identifies CTSK mutations in patients originally diagnosed as intermediate osteopetrosis. Bone 24 24269275
2010 Effect of PstS sub-units or PknD deficiency on the survival of Mycobacterium tuberculosis. Tuberculosis (Edinburgh, Scotland) 22 20933472
2000 The Mycobacterium bovis homologous protein of the Mycobacterium tuberculosis serine/threonine protein kinase Mbk (PknD) is truncated. FEMS microbiology letters 22 10913696
2006 Characterization of the phosphorylation sites of Mycobacterium tuberculosis serine/threonine protein kinases, PknA, PknD, PknE, and PknH by mass spectrometry. Proteomics 20 16739134
2016 Molecular analysis of the CTSK gene in a cohort of 33 Brazilian families with pycnodysostosis from a cluster in a Brazilian Northeast region. European journal of medical research 19 27558267
2009 A single nucleotide polymorphism in the porcine cathepsin K (CTSK) gene is associated with back fat thickness and production traits in Italian Duroc pigs. Molecular biology reports 19 19662513
2018 Articular cartilage protection in Ctsk-/- mice is associated with cellular and molecular changes in subchondral bone and cartilage matrix. Journal of cellular physiology 18 29781506
2009 A mutation in CTSK gene in an autosomal recessive pycnodysostosis family of Pakistani origin. BMC medical genetics 18 19674475
2022 Verteporfin Inhibits the Progression of Spontaneous Osteosarcoma Caused by Trp53 and Rb1 Deficiency in Ctsk-Expressing Cells via Impeding Hippo Pathway. Cells 17 35456040
2022 Deletion of Trp53 and Rb1 in Ctsk-expressing cells drives osteosarcoma progression by activating glucose metabolism and YAP signaling. MedComm 17 35615117
2018 Genetic study of eight Egyptian patients with pycnodysostosis: identification of novel CTSK mutations and founder effect. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 17 29796728
1998 Genomic structure and chromosomal localization of the human cathepsin O gene (CTSO). Genomics 17 9790772
2024 Identification of core immune-related genes CTSK, C3, and IFITM1 for diagnosing Helicobacter pylori infection-associated gastric cancer through transcriptomic analysis. International journal of biological macromolecules 16 39667460
2013 Vaccination with recombinant Mycobacterium tuberculosis PknD attenuates bacterial dissemination to the brain in guinea pigs. PloS one 16 23776655
2020 Associations of Serum Cathepsin K and Polymorphisms in CTSK Gene With Bone Mineral Density and Bone Metabolism Markers in Postmenopausal Chinese Women. Frontiers in endocrinology 15 32117071
2009 A novel inhibitor of Chlamydophila pneumoniae protein kinase D (PknD) inhibits phosphorylation of CdsD and suppresses bacterial replication. BMC microbiology 15 19828035
2015 A Mutation in CTSK Gene in an Autosomal Recessive Pycnodysostosis Family of Chinese Origin. Calcified tissue international 14 25725806
2017 Breast cancer chemoprevention pharmacogenomics: Deep sequencing and functional genomics of the ZNF423 and CTSO genes. NPJ breast cancer 13 28856246
2023 Sfrp4 is required to maintain Ctsk-lineage periosteal stem cell niche function. Proceedings of the National Academy of Sciences of the United States of America 12 37931101
2014 CTSK inhibitor exert its anti-obesity effects through regulating adipocyte differentiation in high-fat diet induced obese mice. Endocrine journal 12 25410008
2010 A novel missense mutation in cathepsin K (CTSK) gene in a consanguineous Pakistani family with pycnodysostosis. Journal of investigative medicine : the official publication of the American Federation for Clinical Research 12 20305575
2011 Familial pycnodysostosis: identification of a novel mutation in the CTSK gene (cathepsin K). Journal of investigative medicine : the official publication of the American Federation for Clinical Research 11 21099701
1999 Complete genomic structure of the mouse cathepsin K gene (Ctsk) and its localization next to the Arnt gene on mouse chromosome 3. Matrix biology : journal of the International Society for Matrix Biology 9 10372556
2021 Phenotypic and genotypic spectrum of CTSK variants in a cohort of twenty-five Indian patients with pycnodysostosis. European journal of medical genetics 8 33945887
2020 Inverse relationship between autophagy and CTSK is related to bovine embryo quality. Reproduction (Cambridge, England) 8 32224503
2013 Novel CTSK mutation resulting in an entire exon 2 skipping in a Thai girl with pycnodysostosis. Pediatrics international : official journal of the Japan Pediatric Society 8 24134756
2024 METTL3 Modulates Ctsk+ Lineage Supporting Cranial Osteogenesis via Hedgehog. Journal of dental research 7 38752256
2024 T-2 toxin induces chondrocyte extracellular matrix degradation by regulating the METTL3-mediated Ctsk m6A modification. International immunopharmacology 7 39426235
2016 Relationship of ZNF423 and CTSO with breast cancer risk in two randomised tamoxifen prevention trials. Breast cancer research and treatment 7 27400912
2022 Altering osteoclast numbers using CTSK models in utero affects mice offspring craniofacial morphology. Orthodontics & craniofacial research 6 36245435
2024 IL-17RA/CTSK axis mediates H. pylori-induced castration-resistant prostate cancer growth. Oncogene 5 39424989
2023 Prediction and therapeutic targeting of the tumor microenvironment-associated gene CTSK in gastric cancer. Discover oncology 5 37930479
2022 Clinical and genetic characterization of three Russian patients with pycnodysostosis due to pathogenic variants in the CTSK gene. Molecular genetics & genomic medicine 5 35315254
2017 Pycnodysostosis: Novel Variants in CTSK and Occurrence of Giant Cell Tumor. Journal of pediatric genetics 5 29441215
2023 Discovery of CTSK+ Periosteal Stem Cells Mediating Bone Repair in Orbital Reconstruction. Investigative ophthalmology & visual science 4 37639249
2021 Phlpp1 is induced by estrogen in osteoclasts and its loss in Ctsk-expressing cells does not protect against ovariectomy-induced bone loss. PloS one 4 34143773
2025 CTSK as a Collagen Degradation Marker Induces Gingival Recession During High-Force Orthodontic Tooth Movement. International dental journal 3 40315697
2023 Andrographolide Alleviates Oxidative Damage and Inhibits Apoptosis Induced by IHNV Infection via CTSK/BCL2/Cytc Axis. International journal of molecular sciences 3 38203479
2019 A Novel Variant c.847T>C in CTSK Gene Leading to Pycnodysostosis: A Case Report. Clinical medicine insights. Case reports 3 30967749
2024 Exosomes derived from mucoperiosteum Krt14+Ctsk+ cells promote bone regeneration by coupling enhanced osteogenesis and angiogenesis. Biomaterials science 2 39392433
2023 Unravelling the Relacatib activity against the CTSK proteins causing pycnodysostosis: a molecular docking and dynamics approach. Journal of biomolecular structure & dynamics 2 37255004
2025 Identification of CTSK as a TLR-related critical biomarker in liver cirrhosis via integrative bioinformatics and pathological characterization. Scientific reports 1 40670571
2025 Ctsk+ Osteoclasts Orchestrate Condylar Morphogenesis via Hypoxic Lysosome. Journal of dental research 1 41108121
2023 A SNP in the ovine cathepsin K (CTSK) gene is associated with yearling growth performance in a crossbred sheep population. Animal biotechnology 1 36752216
2023 Association Between CTSK Gene Polymorphisms and Response to Alendronate Treatment in Postmenopausal Chinese Women with Low Bone Mineral Density. Pharmacogenomics and personalized medicine 1 37920752
2026 Tucatinib alleviates postmenopausal osteoporosis by suppressing osteoclast differentiation via regulating the DRP1/NFATc1/CTSK signaling pathway. Biochemical pharmacology 0 41974330
2025 RANKL, OPG, and CTS-K Release in Bone Response to Immediate Nonfunctional Loading of a Single Implant in Mandibular Molar Sites During Osseointegration Establishment. Clinical and experimental dental research 0 40792611
2025 Cathepsin K (CTSK) in Inflammatory and Immune-Mediated Diseases. Immunological investigations 0 41065357
2025 Liquiritin in Aiduqing formula inhibits breast cancer neoangiogenesis by suppressing CTSK-mediated lysosomal degradation of CXCL1 in tumor-associated macrophages. Phytomedicine : international journal of phytotherapy and phytopharmacology 0 41072283
2025 Mycl, activated by Sgk1-phosphorylated Stat3, mediates osteoclastogenesis via Ctsk transcriptional regulation. Scientific reports 0 41266497
2024 Case Report: A Novel Homozygous Variant of the CTSK Gene in Rare Pycnodysostosis. International journal of molecular sciences 0 39684735
2005 Atypical CTSK transcripts and ARNT transcription read-through into CTSK. Comparative and functional genomics 0 18629217