Cathepsin K Mutations in Skeletal Dysplasia

Cathepsin K is a lysosomal cysteine protease highly expressed in osteoclasts, where it degrades type I collagen and other bone matrix proteins to facilitate normal bone remodelling. Mutations in the CTSK gene lead to the rare autosomal recessive skeletal dysplasia known as pycnodysostosis, characterised by short stature, osteosclerosis, acro-osteolysis of distal phalanges, craniofacial abnormalities and brittle bones prone to pathological fractures. More than thirty distinct CTSK mutations have been identified, predominantly missense changes in the mature enzyme domain, resulting in partial or complete loss of proteolytic activity. Studies of genetically modified mouse models lacking functional Cathepsin K have elucidated its critical role in bone turnover and highlighted secondary effects on immune function and periodontal health. The global distribution of pathogenic variants reflects founder effects in certain populations, emphasising the importance of genetic screening in regions with high consanguinity. Enhanced understanding of the molecular mechanisms underpinning CTSK deficiency has opened avenues for targeted therapies, including small-molecule inhibitors, gene therapy approaches and recombinant enzyme replacement, thus offering hope for improved clinical management and quality of life for affected individuals.

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Cathepsin K Mutations in Skeletal Dysplasia publication trend

The graph below shows the total number of articles in cathepsin k mutations in skeletal dysplasia across all publications each year (not limited to Nature Index journals).

Technical terms

Cathepsin K: A lysosomal cysteine protease essential for osteoclast-mediated bone matrix degradation.

Pycnodysostosis: A rare autosomal recessive skeletal dysplasia caused by loss-of-function mutations in CTSK.

Osteoclast: A specialised bone-resorbing cell that relies on Cathepsin K to degrade collagen.

Acro-osteolysis: Resorption of the distal phalanges commonly observed in pycnodysostosis.

Osteosclerosis: Pathological increase in bone density associated with defective bone resorption.

Missense mutation: A single nucleotide substitution that alters the amino acid sequence of a protein.

Founder effect: The amplification of a genetic variant in a population descended from a small number of individuals.

References

1. Case report: a giant cell-rich gnathic bone lesion in a child with pycnodysostosis. Frontiers in Oral Health (2023).
2. Orthopedic Treatment of Pycnodysostosis: A Systematic Review. Cureus (2022).
3. Clinical and animal research findings in pycnodysostosis and gene mutations of cathepsin K from 1996 to 2011. Orphanet Journal of Rare Diseases (2011).
4. Cathepsin K analysis in a pycnodysostosis cohort: demographic, genotypic and phenotypic features. Orphanet Journal of Rare Diseases (2014).
5. 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 (2016).
6. Increased Bone Resorption during Lactation in Pycnodysostosis. International Journal of Molecular Sciences (2021).