Affinage

CTSK

Cathepsin K · UniProt P43235

Length
329 aa
Mass
37.0 kDa
Annotated
2026-06-09
67 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CTSK encodes cathepsin K, a lysosomal cysteine protease abundantly expressed in osteoclasts that serves as the principal effector of bone matrix degradation, and complete loss-of-function mutations cause the autosomal recessive osteosclerotic dysplasia pycnodysostosis—a phenotype requiring full protein absence rather than partial reduction (PMID:10491211). Disease-causing missense substitutions act through distinct molecular routes: signal-peptide mutations (L7P) disrupt ER targeting and translocation of the nascent enzyme, while active-site-distorting mutations (Y283C) leave protein levels intact but abolish enzymatic activity by perturbing the hydrogen-bond network required for self-cleavage (PMID:17397052, PMID:25731711). CTSK expression is driven by convergent transcriptional programs in osteoclastogenesis: the RUNX2/mTORC2/AKT(Ser473)/NFATc1 axis (PMID:32008052) and the Sgk1/Stat3(Tyr705)/Mycl axis, in which Mycl binds the Ctsk promoter directly (PMID:41266497), with METTL3-mediated m6A modification controlling Ctsk mRNA upstream of Hedgehog signaling in skeletal stem cells (PMID:38752256, PMID:39426235). At the protein-functional level, osteoclast cathepsin K activity depends on HIF-1α-dependent lysosomal biogenesis through the TSC2/mTORC1/TFEB axis, which sustains ruffled-border integrity and matrix remodeling (PMID:41108121). Beyond bone resorption, CTSK marks periosteal and calvarial skeletal stem-cell lineages with multipotent osteogenic capacity (PMID:37931101, PMID:38752256), promotes osteoarthritis progression by regulating MMP-13 and ADAMTS-5 expression (PMID:21968827), drives adipocyte differentiation via PPARγ and C/EBPα (PMID:25410008), mediates TLR9-dependent macrophage inflammatory signaling and autophagy (PMID:31737959, PMID:30636333), and enables lysosomal degradation of CXCL1 in tumor-associated macrophages (PMID:41072283). Cathepsin K is a direct pharmacological target inhibited by tucatinib, which additionally suppresses NFATc1-driven osteoclast differentiation (PMID:41974330).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 High

    Establishing the genomic architecture and transcription start site of CTSK was the prerequisite for understanding its osteoclast-selective expression, and revealed a non-canonical promoter lacking TATA/CAAT elements.

    Evidence FISH, 5' RACE, and ribonuclease protection mapping of the human gene to 1q21

    PMID:9143491

    Open questions at the time
    • Did not identify the transcription factors driving osteoclast-selective expression
    • Promoter mechanism for tissue restriction left undefined
  2. 1999 High

    Reciprocal genotype-phenotype analysis answered whether CTSK is causally required for bone resorption, showing that complete—not partial—loss of cathepsin K causes pycnodysostosis.

    Evidence CTSK sequencing and patient-cell Western blot quantification across affected individuals and carriers

    PMID:10491211

    Open questions at the time
    • Did not resolve how individual missense mutations impair function
    • Non-skeletal consequences of loss not addressed
  3. 1999 Medium

    Mapping the conserved mouse Ctsk locus immediately downstream of Arnt established the syntenic framework that later revealed transcriptional cross-talk between the two genes.

    Evidence Genomic clone isolation and chromosomal mapping in mouse

    PMID:10372556

    Open questions at the time
    • No functional consequence of the Arnt-Ctsk proximity tested
    • Mouse-only structural description
  4. 2005 Medium

    RT-PCR across the ARNT-CTSK intergenic region showed ARNT read-through transcripts extending into CTSK and identified cryptic CTSK promoters, implying transcriptional interference from the neighboring locus.

    Evidence Overlapping RT-PCR, quantitative RT-PCR, and EST analysis across tissues

    PMID:18629217

    Open questions at the time
    • Functional impact of read-through on CTSK output not quantified in osteoclasts
    • Physiological role of alternate transcripts unknown
  5. 2007 Medium

    Functional dissection of missense mutations distinguished defects in protein biogenesis from defects in catalysis, with signal-peptide mutations (L7P) impairing ER targeting and translocation.

    Evidence Transfection/Western blot of mutant CTSK in COS-7 cells plus 3D structural modeling

    PMID:17397052

    Open questions at the time
    • Folding predictions not validated biochemically
    • Did not measure enzymatic activity of each variant
  6. 2015 High

    The Y283C variant resolved a separable class of mutation that preserves expression but ablates enzyme activity by disrupting the hydrogen network required for self-cleavage, linking catalytic loss to dental/cementum phenotypes.

    Evidence COS-7 enzyme activity assays, structural modeling, and patient-tissue histology/micro-CT

    PMID:25731711

    Open questions at the time
    • Self-cleavage defect inferred from modeling rather than direct zymogen processing assay
    • Substrate-level consequences not profiled
  7. 2012 High

    Genetic ablation tested whether cathepsin K contributes to joint disease beyond bone, showing Ctsk-/- mice resist early osteoarthritis with reduced MMP-13 and ADAMTS-5.

    Evidence Ctsk-/- mice in a joint destabilization model with histomorphometry and immunohistochemistry

    PMID:21968827

    Open questions at the time
    • Mechanism linking CTSK to MMP-13/ADAMTS-5 expression not defined
    • Direct versus indirect protease contribution unresolved
  8. 2018 High

    Cell-type-resolved analysis extended the OA role by showing CTSK differentially regulates chondroclastogenesis and subchondral remodeling, with altered osteoclast gene programs.

    Evidence Ctsk-/- DMM model with laser-capture microdissection and targeted PCR arrays of osteoclasts

    PMID:29781506

    Open questions at the time
    • Causal drivers among the differentially expressed genes not isolated
    • Chondroclast versus osteoclast contributions not separated genetically
  9. 2020 High

    Epistasis experiments placed CTSK transcription downstream of a RUNX2/mTORC2/AKT(Ser473)/NFATc1 cascade, explaining how an osteogenic factor controls resorptive gene expression.

    Evidence RAW264.7 lines with WT/mutant RUNX2, AKT inhibition, constitutively active AKT rescue, and resorption assays

    PMID:32008052

    Open questions at the time
    • Direct NFATc1 occupancy of the CTSK promoter not shown in this study
    • In vivo relevance of the axis not tested
  10. 2022 Medium

    Using Ctsk-Cre lineage tracing in a tumor model showed Ctsk-expressing cells can give rise to osteosarcoma via YAP/TEAD1-driven Glut1 upregulation and glucose metabolism.

    Evidence Ctsk-Cre;Trp53/Rb1 conditional knockout, ChIP/promoter binding, and YAP ablation

    PMID:35615117

    Open questions at the time
    • Role of CTSK protease activity itself versus lineage identity not separated
    • Single conditional model
  11. 2023 High

    CTSK was established as a marker of multipotent periosteal/skeletal stem cells, reframing the gene as a lineage identifier beyond mature osteoclasts.

    Evidence Immunostaining, flow cytometry, transcriptomics, and differentiation assays of orbital periosteal CTSK+ cells; Sfrp4 deletion in Ctsk-lineage PSCs

    PMID:37639249 PMID:37931101

    Open questions at the time
    • Functional requirement of CTSK protein in stem-cell behavior not directly tested
    • Relationship between CTSK+ stem cells and CTSK+ osteoclasts unresolved
  12. 2024 High

    MeRIP-seq defined post-transcriptional control of Ctsk by METTL3-mediated m6A modification, placing the METTL3/m6A/Ctsk axis upstream of Hedgehog signaling in skeletal stem cells and of ECM homeostasis in cartilage.

    Evidence Ctsk-lineage Mettl3 conditional knockout with Hh rescue, plus MeRIP-seq and siRNA in toxin-induced cartilage degradation

    PMID:38752256 PMID:39426235

    Open questions at the time
    • The reader protein interpreting Ctsk m6A marks not identified
    • Whether m6A alters CTSK protein activity or only abundance unclear
  13. 2019 Medium

    Knockdown and pharmacological inhibition revealed a non-canonical inflammatory role, placing Ctsk upstream of TLR9-mediated autophagy and cytokine production in macrophages.

    Evidence AAV/siRNA knockdown and BML-244 inhibition in periodontitis-RA models with TLR9 agonist stimulation

    PMID:30636333 PMID:31737959

    Open questions at the time
    • Molecular substrate connecting CTSK to TLR9 not identified
    • Single lab; protease-dependence of the effect not established
  14. 2025 High

    Two genetic mouse models showed osteoclast CTSK function depends on HIF-1α-driven lysosomal biogenesis via TSC2/mTORC1/TFEB, linking protein-level regulation to ruffled-border integrity and condylar morphogenesis.

    Evidence Ctsk+ cell ablation and HIF-1α conditional knockout with EM of ruffled borders/lysosomes and pathway analysis

    PMID:41108121

    Open questions at the time
    • Direct measurement of CTSK activity in HIF-1α-null osteoclasts not reported
    • Mechanism of biphasic cartilage phenotype incompletely defined
  15. 2025 High

    A promoter-binding study defined the Sgk1-Stat3(Tyr705)-Mycl axis controlling Ctsk transcription, with Mycl directly occupying the Ctsk promoter, adding a second transcriptional input to osteoclastogenesis.

    Evidence Sgk1 inhibition, Stat3 phospho-Western, Mycl overexpression rescue, ChIP, and trabecular bone micro-CT

    PMID:41266497

    Open questions at the time
    • Interplay with the RUNX2/NFATc1 axis not integrated
    • Mycl-binding site specificity not finely mapped
  16. 2025 Medium

    Proteomics of CTSK-depleted trabecular meshwork cells extended CTSK function to ECM/collagen homeostasis and actin organization via a calcium/PRKD1/LIMK1/SSH1/cofilin pathway.

    Evidence siRNA knockdown in human TM cells with unbiased proteomics, calcium measurement, and pathway analysis (preprint)

    PMID:bio_10.1101_2025.02.10.637394

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Direct protease substrates driving the actin remodeling not identified
  17. 2025 Medium

    A drug-induced gain-of-function context showed CTSK can drive lysosomal degradation of the chemokine CXCL1 in tumor-associated macrophages, suppressing breast-cancer neoangiogenesis.

    Evidence Liquiritin treatment with CXCL1-lysosome colocalization, CXCL1 overexpression rescue, and zebrafish/murine xenografts

    PMID:41072283

    Open questions at the time
    • Whether CXCL1 is a direct CTSK substrate not biochemically demonstrated
    • Single lab; physiological (non-drug) relevance unclear
  18. 2026 High

    Direct binding studies validated CTSK as a druggable target of tucatinib while revealing a parallel DRP1/NFATc1 mitochondrial mechanism in osteoclast inhibition.

    Evidence Microscale thermophoresis, molecular docking, CTSK activity assay, DRP1 phospho-Western, mtROS, and ovariectomized mouse model

    PMID:41974330

    Open questions at the time
    • Relative contribution of direct CTSK inhibition versus DRP1/NFATc1 effect to bone outcome unquantified
    • Selectivity against other cathepsins not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the physiological substrate repertoire of cathepsin K beyond bone collagen (e.g., CXCL1, ECM components in TM and cartilage) is selected, and how its multiple transcriptional and post-transcriptional inputs are integrated across the osteoclast versus skeletal-stem-cell states.
  • Direct substrate identification for non-bone roles lacking
  • Integration of RUNX2/NFATc1, Sgk1/Mycl, and METTL3/m6A inputs not unified
  • Structural basis of substrate specificity not addressed in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016787 hydrolase activity 2
Localization
GO:0005764 lysosome 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-168256 Immune System 3

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 CTSK (cathepsin K) was mapped to chromosome 1q21, spans ~12.1 kb, contains eight exons and seven introns, and has a single transcriptional start site 49 bp upstream of the initiator Met codon; the 5' flanking region lacks canonical TATA and CAAT boxes, suggesting a non-canonical promoter mechanism for osteoclast-selective expression. Fluorescence in situ hybridization (FISH), PCR on genomic DNA, ribonuclease protection assay, 5' RACE, P1 genomic clone isolation Genomics High 9143491
1999 Loss-of-function mutations in CTSK (a premature stop codon K52X and a missense G79E) result in virtually absent cathepsin K protein in affected individuals and cause pycnodysostosis, an autosomal recessive osteosclerotic skeletal dysplasia; heterozygous carriers with 50-80% reduced protein levels show no phenotype, demonstrating that complete absence—not partial reduction—of cathepsin K is required for disease. DNA sequencing of CTSK gene, Western blot protein quantification in patient-derived cells Journal of bone and mineral research High 10491211
1999 The mouse cathepsin K gene (Ctsk) spans 10.1 kb with eight exons and seven introns, and is located approximately 4.5 kb downstream of the Arnt gene on mouse chromosome 3, with the genomic structure conserved between human and mouse. Genomic clone isolation, sequence analysis, chromosomal mapping Matrix biology Medium 10372556
2005 ARNT transcripts can read through the intergenic region and extend into CTSK as far as CTSK intron 3 (~3.7 kb downstream of the end of the longest previously described ARNT mRNA), potentially interfering with CTSK expression; novel CTSK transcripts with alternate 5' splicing and a cryptic upstream promoter were also identified. RT-PCR overlapping ARNT 3' end and CTSK 5' end, quantitative RT-PCR, EST sequence analysis Comparative and functional genomics Medium 18629217
2007 Nine novel CTSK missense mutations cause pycnodysostosis; the L7P mutation within the predicted hydrophobic signal peptide domain significantly reduced cathepsin K protein expression in transfected COS-7 cells, indicating the mutation disrupts targeting and translocation of the nascent lysosomal protein across the ER membrane; all six novel missense mutations were predicted to cause incorrect protein folding based on 3D structural modeling. Western blot of COS-7 cells transfected with mutant CTSK, 3D structural modeling Human mutation Medium 17397052
2012 Ctsk knockout (Ctsk-/-) mice show significantly delayed OA progression in a joint destabilization model, with reduced MMP-13 and ADAMTS-5 expression in chondrocytes and synovial cells, demonstrating that cathepsin K plays a direct role in early-to-intermediate osteoarthritis development, likely through regulating downstream matrix metalloproteinase expression. Ctsk-/- knockout mouse model, joint destabilization surgery, histomorphometry, immunohistochemistry for CTK/MMP-13/ADAMTS-5/TRAP Arthritis and rheumatism High 21968827
2015 The CTSK missense mutation Y283C does not affect mRNA or protein levels of overexpressed CTSK in COS-7 cells but significantly reduces CTSK enzyme activity; 3D structural modeling indicates loss of the hydroxybenzene residue disrupts the hydrogen network and affects self-cleavage of the enzyme. These mutations cause thickened and softened cementum with cementocyte accumulation and disorganized alveolar bone structure in affected patients. COS-7 transfection, CTSK enzyme activity assay, RT-PCR, western blot, 3D structure modeling, histological staining (H&E, toluidine blue), atomic force microscopy, micro-CT Journal of dental research High 25731711
2018 Ctsk-/- mice undergoing destabilization of the medial meniscus (DMM) show delayed subchondral and calcified cartilage remodeling by osteoclasts and chondroclasts; Ctsk-/- mice have fewer growth plate-derived chondroclasts than WT during OA, suggesting cathepsin K differentially regulates chondroclastogenesis. PCR arrays of laser-captured osteoclasts identified differential expression of Atp6v0d2, Tnfrsf11a, Ca2, Calcr, Ccr1, Gpr68, Itgb3, Nfatc1, and Syk between WT and Ctsk-/- mice. Ctsk-/- knockout mouse model, DMM surgery, histomorphometry, TRAP staining, laser capture microdissection followed by targeted PCR arrays Journal of cellular physiology High 29781506
2019 Ctsk inhibition by adeno-associated virus (AAV) knockdown reduces TLR9 signaling, autophagy proteins (TFEB and LC3), and inflammatory cytokines in a periodontitis-with-RA mouse model; in vitro, Ctsk inhibition suppresses TLR9 downstream signaling and autophagy-related proteins in macrophages stimulated by CpG ODN (TLR9 agonist), placing Ctsk upstream of TLR9-mediated autophagy. AAV-mediated CTSK knockdown in vivo, siRNA knockdown in macrophages, micro-CT, IHC, western blot, qRT-PCR, immunofluorescence Cell proliferation Medium 31737959
2019 Inhibition of Ctsk with BML-244 reduces TLR4 and TLR9 expression in vivo and specifically suppresses cytokine production in response to TLR9 engagement in vitro in a periodontitis-RA comorbidity model, confirming Ctsk as a mediator of TLR9 pathway signaling. Pharmacological Ctsk inhibition (BML-244) in DBA/1 mouse model, in vitro cytokine assays, bone erosion measurement Journal of clinical periodontology Medium 30636333
2020 RUNX2 promotes osteoclast differentiation and bone resorption through the AKT/NFATc1/CTSK axis: wild-type RUNX2 increases mTORC2 activity, which specifically phosphorylates AKT at Ser473, promoting NFATc1 nuclear translocation and upregulating CTSK expression; AKT inhibition abrogates osteoclast formation, while constitutively activated AKT rescues differentiation impaired by mutant RUNX2. Stable RAW264.7 cell lines expressing WT or mutant RUNX2, F-actin ring formation assay, bone resorption assay, western blot for mTORC2/AKT/NFATc1/CTSK, AKT inhibition and constitutively active AKT rescue experiments Calcified tissue international High 32008052
2022 Loss of Trp53 and Rb1 in Ctsk-expressing cells drives osteosarcoma progression via elevated YAP expression and activity; YAP/TEAD1 complex binds the Glut1 promoter to upregulate glucose transporter 1 expression, increasing glucose metabolism; ablation of YAP signaling inhibited energy metabolism and delayed osteosarcoma progression in the Ctsk-Cre;Trp53f/f/Rb1f/f mouse model. Ctsk-Cre conditional knockout mouse model, ChIP/promoter binding assay (YAP/TEAD1 to Glut1 promoter), YAP ablation experiments, micro-CT, mechanistic Western blot MedComm Medium 35615117
2023 Cathepsin K (CTSK)-positive periosteal stem cells (PSCs) in the orbital periosteum coexpress CD200 and colocalize with osteocalcin in the inner periosteal layer, demonstrate multipotent differentiation capacity, and are mobilized after orbital fracture; transcriptome sequencing revealed 3613 differentially expressed genes between CTSK+ PSCs and bone marrow MSCs, with PSCs showing enriched pathways for intramembranous osteogenesis. Immunofluorescence, immunohistochemistry, flow cytometry, transcriptome sequencing, multidirectional differentiation assays, GO analysis Investigative ophthalmology & visual science Medium 37639249
2023 Sfrp4 is expressed in Ctsk-lineage periosteal stem cells (PSCs) and its deletion decreases the PSC pool, impairs clonal multipotency for osteoblast and chondrocyte differentiation, hampers periosteal response to bone injury, and abolishes PTH-dependent increases in PSC number and cortical bone formation; bulk RNA sequencing showed Sfrp4 deletion downregulates pathways for skeletal development and bone mineralization in Ctsk-lineage cells. Sfrp4 global deletion mouse model, flow cytometry for PSC quantification, clonal differentiation assays, bone organoid formation, periosteal injury model, PTH treatment, bulk RNA sequencing of Ctsk-lineage cells PNAS High 37931101
2024 METTL3-mediated m6A modification of Ctsk mRNA regulates Ctsk+ calvarial stem cell (CSC) function; depletion of Mettl3 in Ctsk+ lineage cells delayed suture formation, decreased mineralization, impaired calvarial bone formation, and reduced Hedgehog (Hh) signaling; restoration of Hh signaling by genetic or pharmacological means partially rescued the abnormality, placing METTL3/m6A/Ctsk upstream of Hh signaling in CSCs. Ctsk-lineage-specific Mettl3 conditional knockout, MeRIP-seq, RNA-seq, micro-CT, histomorphometry, genetic and pharmacological Hh pathway rescue (Sufu crossing, SAG21 administration) Journal of dental research High 38752256
2024 T-2 toxin induces cartilage extracellular matrix degradation via METTL3-mediated m6A methylation of Ctsk mRNA; silencing METTL3 increases Ctsk expression and worsens ECM degradation, while increasing m6A methylation via dietary methionine supplementation mitigates cartilage damage; silencing Ctsk itself also aggravated HT-2 toxin-induced ECM degradation, defining the METTL3/m6A/Ctsk axis in cartilage homeostasis. MeRIP sequencing, RNA sequencing, siRNA knockdown of METTL3 and Ctsk, in vivo methionine supplementation, ECM degradation assays International immunopharmacology High 39426235
2025 Loss of CTSK in trabecular meshwork (TM) cells (siRNA knockdown) significantly disrupts collagen biogenesis and ECM homeostasis, increases intracellular calcium levels, and activates PRKD1, which enhances actin polymerization through the LIMK1/SSH1/cofilin pathway and promotes focal adhesion maturation; RhoQ and myosin motor proteins are significantly downregulated, indicating altered mechanotransduction. siRNA-mediated CTSK knockdown in human TM cells, unbiased proteomics, calcium level measurement, pathway analysis bioRxiv (preprint)preprint Medium bio_10.1101_2025.02.10.637394
2025 Ctsk+ osteoclasts regulate condylar morphogenesis through HIF-1α-dependent lysosomal biogenesis via the TSC2-mTORC1-TFEB axis; conditional knockout of HIF-1α in Ctsk+ cells causes disorganized ruffled borders and defective lysosomal biogenesis in osteoclasts, leading to cartilage accumulation at early timepoints and paradoxical cartilage reduction with accelerated subchondral mineralization at later timepoints. DTR transgenic mouse ablation of Ctsk+ cells, HIF-1α conditional knockout in Ctsk+ cells (HIF-1α∆ctsk-cre), histomorphometry, immunohistochemistry, electron microscopy of ruffled borders and lysosomes, mechanistic pathway analysis Journal of dental research High 41108121
2025 Mycl, a MYC family transcription factor activated downstream of Sgk1-phosphorylated Stat3 (at Tyr705), directly binds the Ctsk promoter to regulate its transcription during osteoclastogenesis; Mycl overexpression rescues osteoclast differentiation impaired by Sgk1 inhibition, defining the Sgk1-Stat3-Mycl-Ctsk signaling axis. Sgk1 inhibitor (GSK650394) treatment, Stat3 phosphorylation western blot, Mycl overexpression rescue experiments, ChIP/promoter binding assay (Mycl to Ctsk promoter), in vivo micro-CT of trabecular bone mass Scientific reports High 41266497
2026 Tucatinib directly binds and inhibits CTSK (confirmed by microscale thermophoresis, molecular docking, and CTSK activity assays) and also suppresses NFATc1-driven osteoclast differentiation by inhibiting DRP1 phosphorylation at Ser616, reducing mitochondrial ROS and stabilizing mitochondrial fission/fusion dynamics, thereby defining a dual DRP1/NFATc1/CTSK axis in osteoclastic bone resorption. Microscale thermophoresis (direct binding), molecular docking, CTSK enzymatic activity assay, DRP1 phosphorylation western blot, mtROS measurement, ovariectomized mouse model, bone marrow-derived monocyte/macrophage differentiation assays Biochemical pharmacology High 41974330
2025 Liquiritin upregulates CTSK expression in tumor-associated macrophages (TAMs), causing CXCL1 to colocalize with lysosomes and undergo accelerated lysosomal degradation; this CTSK-mediated lysosomal degradation of CXCL1 suppresses TAM-induced breast cancer neoangiogenesis in vitro and in vivo. LC-MS screening, CXCL1 ELISA, lysosome/CXCL1 colocalization imaging, CTSK expression analysis, CXCL1 overexpression rescue, zebrafish xenotransplantation, murine xenograft model Phytomedicine Medium 41072283
2014 CTSK selective inhibitor (CKSI) treatment in high-fat diet obese mice reduces adipose tissue weight gain, improves insulin sensitivity, and significantly downregulates PPARγ and C/EBPα expression—key transcription factors for adipogenic differentiation—demonstrating that CTSK promotes adipocyte differentiation through regulation of these transcription factors. Pharmacological CTSK inhibition in HFD-induced obese C57BL/6 mice, adipose tissue weight measurement, HOMA index, histological analysis of adipocyte size, western blot/qPCR for PPARγ and C/EBPα Endocrine journal Medium 25410008

Source papers

Stage 0 corpus · 67 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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 68 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 49 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 39 9143491
2019 Inhibition of Ctsk alleviates periodontitis and comorbid rheumatoid arthritis via downregulation of the TLR9 signalling pathway. Journal of clinical periodontology 36 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
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
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 20 19662513
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
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
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 17 39667460
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
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
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
2020 Inverse relationship between autophagy and CTSK is related to bovine embryo quality. Reproduction (Cambridge, England) 10 32224503
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
2024 METTL3 Modulates Ctsk+ Lineage Supporting Cranial Osteogenesis via Hedgehog. Journal of dental research 8 38752256
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
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 T-2 toxin induces chondrocyte extracellular matrix degradation by regulating the METTL3-mediated Ctsk m6A modification. International immunopharmacology 7 39426235
2022 Altering osteoclast numbers using CTSK models in utero affects mice offspring craniofacial morphology. Orthodontics & craniofacial research 7 36245435
2024 IL-17RA/CTSK axis mediates H. pylori-induced castration-resistant prostate cancer growth. Oncogene 6 39424989
2023 Prediction and therapeutic targeting of the tumor microenvironment-associated gene CTSK in gastric cancer. Discover oncology 6 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
2025 CTSK as a Collagen Degradation Marker Induces Gingival Recession During High-Force Orthodontic Tooth Movement. International dental journal 4 40315697
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
2024 Exosomes derived from mucoperiosteum Krt14+Ctsk+ cells promote bone regeneration by coupling enhanced osteogenesis and angiogenesis. Biomaterials science 3 39392433
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
2023 A SNP in the ovine cathepsin K (CTSK) gene is associated with yearling growth performance in a crossbred sheep population. Animal biotechnology 2 36752216
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 Cathepsin K (CTSK) in Inflammatory and Immune-Mediated Diseases. Immunological investigations 1 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 1 41072283
2025 Ctsk+ Osteoclasts Orchestrate Condylar Morphogenesis via Hypoxic Lysosome. Journal of dental research 1 41108121
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 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

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