HGNC Approved Gene Symbol: CTSK
SNOMEDCT: 89647000;
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38) : 1:150,796,208-150,808,260 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.3 | Pycnodysostosis | 265800 | Autosomal recessive | 3 |
Cathepsin K (EC 3.4.22.38), a member of the papain family of cysteine proteinases, plays an important role in osteoclast function (Gelb et al., 1996).
Shi et al. (1995) isolated a cysteine proteinase, the expression of which was dramatically upregulated during the in vitro maturation of peripheral blood monocytes into macrophages. Because the human macrophage-derived cDNA bore strong homology to a putative cysteine protease isolated from rabbit osteoclasts called OC2, they called the human enzyme cathepsin O (CTSO). Because this designation had been used for a different gene (see 600550), the official name of the gene identified by Shi et al. (1995) became cathepsin K. The cathepsin K cDNA produces a single 1.7-kb transcript as detected on Northern blots of 15-day-old monocyte-derived macrophage RNA, but was not expressed in human monocytes or alveolar macrophages. The cDNA predicted a 329-amino acid preprocathepsin with more than 50% identity to both cathepsin S (CTSS; 116845) and cathepsin L (CTSL; 116880) of the human and 94% identity to rabbit OC2.
Inaoka et al. (1995) also cloned a human cDNA for cathepsin K using a probe for the previously isolated rabbit sequence. Highest expression was noted in osteoarthritic hip bones and especially in an osteoclastoma. The authors proposed that this cathepsin may be an important component of human osteoclastic bone resorption whose pathologies include osteoporosis and osteoarthritis.
Rantakokko et al. (1996) used Northern blot analysis and in situ hybridization of mouse tissues to identify the specific cell types expressing cathepsin K. They found the highest levels of expression in musculoskeletal tissues: bone, cartilage, and skeletal muscle. The strongest in situ signals were seen in osteoclasts and, to a lesser extent, in some hypertrophic chondrocytes.
Gelb et al. (1997) and Rood et al. (1997) described the genomic organization of the CTSK gene.
Gelb et al. (1997) and Rood et al. (1997) mapped the CTSK gene to chromosome 1q21 by fluorescence in situ hybridization. Gelb et al. (1997) mapped CTSK within 150 kb of CTSS.
Shi et al. (1995) found that human CTSK displayed potent endoprotease activity against fibrinogen at acid pH when expressed in COS-7 cells. They speculated that this endoprotease may play a role in extracellular matrix degradation.
Rantakokko et al. (1996) suggested that cathepsin K is associated with the degradation of bone and cartilage.
In addition to its high expression in osteoclasts, where it plays an essential role in the degradation of protein components of bone matrix, cathepsin K is expressed in a significant fraction of human breast cancers, where it could contribute to tumor invasiveness (Littlewood-Evans et al., 1997).
Using transcriptomic analysis, Kubler et al. (2016) showed that several collagen-degrading proteases, including Mmp1 (120353), Mmp13 (600108), Mmp14 (600754), Cma1 (118938), and Ctsk, were highly upregulated in a rabbit cavitary tuberculosis (TB; see 607948) model. Ctsk was the most upregulated type I collagenase in both cavitary and granulomatous tissue, as assessed by RT-PCR and immunohistochemical analysis, and the authors noted that it is unique in its ability to cleave type I collagen (see COL1A1, 120150) inside and outside the helical region. Serum levels of CICP and free urinary deoxypyridinoline, turnover products of type I collagen, were increased, whereas urinary helical peptide was decreased, in rabbits with terminal cavities. Expression of Col1a1, Col1a2 (120160), and Col3a1 (120180) was increased in cavity wall tissue. Immunohistochemical analysis demonstrated CTSK expression in mononuclear and multinucleated giant cells at the periphery of pulmonary lesions and cavity surfaces in patients with TB. Plasma CTSK was significantly higher in patients with active TB compared with healthy controls. Kubler et al. (2016) proposed that CTSK-mediated collagen degradation plays an important role in cavity formation in TB.
Pycnodysostosis (265800), an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature, maps to 1q21 in the same region as cathepsin K. In this disorder, osteoclasts, which are involved in bone resorption, are normal in numbers as are their ruffled borders and clear zones, but the region of demineralized bone surrounding individual osteoclasts is increased. Ultrastructural studies demonstrate that pycnodysostosis osteoclasts function normally in demineralizing bone but do not adequately degrade the organic matrix. Cathepsin K, a cysteine protease that is highly expressed in osteoclasts, was a logical candidate for the site of the defect in this skeletal dysplasia. Gelb et al. (1996) identified nonsense, missense, and stop codon mutations in the gene encoding cathepsin K in patients with pycnodysostosis. Transient expression of complementary DNA containing the stop codon mutation resulted in mRNA but no immunologically detectable protein. The findings suggested that cathepsin K is a major lysosomal protease in bone resorption, providing a possible rationale for the treatment of disorders such as osteoporosis and certain forms of arthritis.
In affected individuals from 8 unrelated families with pycnodysostosis, Hou et al. (1999) identified homozygosity for 8 different mutations in the cathepsin K gene. Functional studies of mutant and wildtype enzyme suggested that the cathepsin K active site contains a critical collagen-binding domain.
In Denmark, Haagerup et al. (2000) studied pycnodysostosis in 5 independent families. They found 2 new mutations and 1 previously described mutation. In 3 of the families, patients were homozygous for a 926T-C transition in exon 8, causing a leu309-to-pro amino acid substitution (601105.0007). In the remaining 2 families, the patients were compound heterozygous for the 926T-C mutation and another novel mutation in each case. In a study of 150 healthy controls, Haagerup et al. (2000) found a frequency of 1 in 150 for the 926T-C mutation and below 1 in 300 for the other 2 mutations. One patient from each family was haplotyped with 8 microsatellite markers surrounding the cathepsin K gene on 1q21. A very rare haplotype constituted a highly conserved area around the disease locus in all patients. This haplotype was found on 7 chromosomes identical by state out of the possible 8 carrying the 926T-C mutation. Founder effect and locus homogeneity within this population were discussed. The first pregnancy and delivery in a patient with pycnodysostosis was reported. Despite the common haplotype, the 5 nuclear families could not be shown to be related on tracing 4 generations back.
Lazner et al. (1999) reviewed their own work and that of others on the cathepsin K knockout mouse. Targeted mutation of the Ctsk gene in mice resulted in many of the phenotypic features of pycnodysostosis, including increased bone density and bone deformity. Radiographic analysis of these mice revealed that the phenotype also became progressively pronounced with age, as does the osteopetrosis associated with pycnodysostosis. Both the human disease and the cathepsin K knockout mouse display a bias towards abnormalities in bones that are rapidly remodeled during normal bone development and homeostasis. The bones that are more resistant to osteoporotic changes following ovariectomy and orchidectomy in mice are the same as those that do not appear to be susceptible to osteopetrosis in the cathepsin K knockout mouse and in pycnodysostosis. Splenomegaly was observed in a subset of the cathepsin K knockout mice; splenomegaly and anemia have been described in pycnodysostosis (Norman and Dubowy, 1971).
MITF (156845) is a member of a helix-loop-helix transcription factor subfamily, which contains the potential dimerization partners TFE3 (314310), TFEB (600744), and TFEC (604732). In mice, dominant-negative, but not recessive, mutations of Mitf produce osteopetrosis (see 166600), suggesting a functional requirement for other family members. MITF also has been found--and TFE3 has been suggested--to modulate age-dependent changes in osteoclast function. There is a phenotypic similarity between microphthalmia Mitf mi/mi mutant mice and cathepsin K-null mice (Saftig et al., 1998; Gowen et al., 1999), as well as the human disease pycnodysostosis caused by deficiency of cathepsin K. Motyckova et al. (2001) identified cathepsin K as a transcriptional target of MITF and TFE3 via 3 consensus elements in the cathepsin K promoter. Additionally, cathepsin K mRNA and protein were deficient in Mitf mutant osteoclasts, and overexpression in wildtype Mitf dramatically upregulated expression of endogenous cathepsin K in cultured human osteoclasts. Cathepsin K promoter activity was disrupted by dominant-negative, but not recessive, mouse alleles of Mitf in a pattern that closely matches their osteopetrotic phenotypes. This relationship between cathepsin K and the Mitf family helps explain the phenotypic overlap of their corresponding deficiencies in pycnodysostosis and osteopetrosis and identifies likely regulators of cathepsin K expression in bone homeostasis and human malignancy.
Chen et al. (2007) found that development of pycnodysostosis in cathepsin K -/- mice depended on the genetic background. Cathepsin K knockout in the 129/Sv inbred strain, but not in the C57BL/6J inbred strain, resulted in features that mimicked human pycnodysostosis, including short stature, osteopetrosis, acroosteolysis, bone fragility, separated cranial sutures with open fontanelles, and loss of mandibular angle. 129/Sv cathepsin K -/- mice also exhibited spondylolysis in vertebrae, thin calvarial bones, abnormal tooth development, and lack of occlusion due to an enhanced open bite. 129/Sv cathepsin K -/- mice showed significantly increased numbers of osteoclasts compared with wildtype mice, and bone resorption appeared to be downregulated in long bones and upregulated in calvaria, phalanges, and vertebrae of 129/Sv cathepsin K -/- mice. Cathepsin K knockout did not alter osteoclast-mediated extracellular acidification, but it impaired the ability of osteoclasts to degrade collagen. Cathepsin K -/- preosteoclasts were resistant to apoptosis and showed impaired senescence and an enhanced ability to tolerate passage in culture compared with wildtype preosteoclasts. Overexpression of cathepsin K initiated senescence in mouse preosteoclasts and rat osteosarcoma cells and increased expression of p19 (600160), p53 (191170), and p21 (CDKN1A; 116899).
Asagiri et al. (2008) showed that inhibition of cathepsin K could potently suppress autoimmune inflammation of the joints as well as osteoclastic bone resorption in autoimmune arthritis. Furthermore, cathepsin K-null mice were resistant to experimental autoimmune encephalomyelitis. Pharmacologic inhibition or targeted disruption of cathepsin K resulted in defective Toll-like receptor-9 (TLR9; 605474) signaling in dendritic cells in response to unmethylated CpG cDNA, which in turn led to attenuated induction of T helper-17 (Th17) cells without affecting the antigen-presenting ability of dendritic cells. Asagiri et al. (2008) suggested that cathepsin K plays an important role in the immune system and may serve as a valid therapeutic target in autoimmune diseases.
Yang et al. (2013) crossed conditional Ptpn11 (176876) knockout (Ptpn11(fl)) mice expressing Cre under the control of the endogenous lysozyme (LysM; 153450) or cathepsin K (Ctsk) promoter. The LysM promoter is active in monocytes, macrophages, and osteoclast precursors, whereas the Ctsk promoter was thought to be active only in mature osteoclasts. While LysMCre;Ptpn11(fl/fl) mice had mild osteopetrosis, CtskCre;Ptpn11(fl/fl) mice developed features very similar to metachondromatosis (156250), caused by mutation in the PTPN11 gene. Lineage tracing revealed a novel population of CtskCre-expressing cells in the perichondrial groove of Ranvier that display markers and functional properties consistent with mesenchymal progenitors (Ctsk+ chondroid progenitors, or CCPs). Chondroid neoplasms arise from these cells and show decreased extracellular signal-regulated kinase (ERK) pathway activation, increased Indian hedgehog (Ihh; 600726) and parathyroid hormone-related protein (Pthrp; 168470) expression and excessive proliferation. Shp2-deficient chondroprogenitors had decreased fibroblast growth factor (FGF)-evoked ERK activation and enhanced Ihh and Pthrp expression, whereas fibroblast growth factor receptor (FGFR; see 136350) or mitogen-activated protein kinase kinase (MEK; see 176872) inhibitor treatment of chondroid cells increased Ihh and Pthrp expression. Importantly, smoothened (601500) inhibitor treatment ameliorated metachondromatosis features in the CtskCre;Ptpn11(fl/fl) mice. Yang et al. (2013) concluded that thus, in contrast to its prooncogenic role in hematopoietic and epithelial cells, Ptpn11 is a tumor suppressor in cartilage, acting through a FGFR/MEK/ERK-dependent pathway in a novel progenitor cell population (CCPs) to prevent excessive Ihh production.
In 2 Israeli Arab pycnodysostosis (265800) patients, Gelb et al. (1996) used RT-PCR amplification and sequencing of the cathepsin K transcript from lymphoblast total RNA to demonstrate an A-to-G transition at cDNA nucleotide 1095, which predicted the substitution of the termination codon by a tryptophan residue (X330W) and the elongation of the C terminus by 19 additional amino acids. Evaluation of the X330W allele in the entire Israeli Arab pycnodysostosis family and in 43 unrelated normal Arab control individuals revealed that it cosegregated with disease in the pycnodysostosis family and was not present in any of the 86 Arab control alleles.
In 2 Moroccan Arab sibs with pycnodysostosis (265800), Gelb et al. (1996) demonstrated a missense mutation, a G-to-C transversion at nucleotide 541, predicting a gly146-to-arg (G146R) substitution.
In an American Hispanic pycnodysostosis (265800) patient with nonconsanguineous parents, Gelb et al. (1996) found heteroallelism for the G146R mutation (601105.0002) and a C-to-T transition of a CpG dinucleotide at nucleotide 826 of their cDNA sequence, predicting an arg241-to-ter (R241X) nonsense mutation. Restriction analysis of amplified segments from genomic DNA with BamI for G146R and AvaI for R241X confirmed the RT-PCR results.
Johnson et al. (1996) found this same mutation in homozygous state in a consanguineous Mexican kindred in which Polymeropoulos et al. (1995) mapped pycnodysostosis to 1q21. Johnson et al. (1996) stated that codon 241 was affected but designated the point mutation as being at nucleotide 862 of the gene sequence they used (GenBank S79895).
In a 7-year-old boy with pycnodysostosis (265800), Gelb et al. (1997, 1998) identified the first example of uniparental disomy (UPD) involving chromosome 1. The child had typical features of pycnodysostosis, although he had nearly normal stature. He had idiopathic hypercalciuria, also present in the father, but no other medical problems and was developmentally normal. Informative simple tandem repeat markers (STRs), from 1q21 and later from the entire chromosome 1, showed a single paternal allele but no maternal allele in the patient. Sequencing of the cathepsin K gene in the patient revealed a C-to-T transition of nucleotide 935, predicting the substitution of an alanine by a valine at residue 277. Using an AciI site destroyed by the mutation, the patient was confirmed as a homozygote; the father was a heterozygote, and the mother was normal. The lack of an observable phenotype that could be attributed to the UPD confirmed previous predictions that human chromosome 1 is not imprinted. The UPD was thought to have resulted from nondisjunction secondary to a meiosis II error since STRs close to the centromere were homoallelic while more telomeric markers were heteroallelic. The ala277-to-val cathepsin K mutation, affecting a highly conserved residue, appeared to be a minor substitution, perhaps explaining the nearly normal stature of the patient.
In 2 sibs with pycnodysostosis (265800), Ho et al. (1999) identified compound heterozygosity for 2 mutations in the CTSK gene: a G-to-A transition at nucleotide 236, resulting in a gly79-to-glu substitution, and an A-to-T transition at nucleotide 154, resulting in a lys52-to-ter substitution (601105.0006). Sequencing of genomic and cDNA from the parents demonstrated that the missense mutation was inherited from the father and the nonsense mutation from the mother. Protein expression in both affected children was virtually absent, while in the parents it was reduced by 50 to 80% compared with controls.
For discussion of the lys52-to-ter (K52X) mutation in the CTSK gene that was found in compound heterozygous state in 2 sibs with pycnodysostosis (265800) by Ho et al. (1999), see 601105.0005.
Of 5 ostensibly unrelated pycnodysostosis (265800) families in Denmark, Haagerup et al. (2000) found that affected members in 3 families were homozygous for a 926T-C transition in exon 8 of the CTSK gene, resulting in a leu309-to-pro (L309P) mutation, whereas affected members in the 2 other families were compound heterozygotes with this mutation and, in each case, a second novel mutation. A very rare haplotype was found in 7 of 8 chromosomes carrying the 926T-C mutation underlying the L309P amino acid substitution.
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