Pycnodysostosis, a Lysosomal Disease Caused by Cathepsin K Deficiency

TLDR

Pycnodysostosis is an autosomal recessive osteochondrodysplasia marked by osteosclerosis and short stature, linked to chromosome 1q21 where the highly expressed osteoclast cathepsin K gene resides. Mutations in the cathepsin K gene abolish protein expression, proving that pycnodysostosis results from defects in this lysosomal protease and underscoring cathepsin K as a key bone‑resorption enzyme with therapeutic potential for osteoporosis and arthritis.

Abstract

Pycnodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature, maps to chromosome 1q21. Cathepsin K, a cysteine protease gene that is highly expressed in osteoclasts, localized to the pycnodysostosis region. Nonsense, missense, and stop codon mutations in the gene encoding cathepsin K were identified in patients. Transient expression of complementary DNA containing the stop codon mutation resulted in messenger RNA but no immunologically detectable protein. Thus, pycnodysostosis results from gene defects in a lysosomal protease with highest expression in osteoclasts. These findings suggest that cathepsin K is a major protease in bone resorption, providing a possible rationale for the treatment of disorders such as osteoporosis and certain forms of arthritis.