Pycnodysostosis, a Lysosomal Disease Caused by Cathepsin K Deficiency

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.

Expression of Matrix-Degrading Cysteine Proteinase Cathepsin K in Cholesteatoma

“…Furthermore, it has been shown to be unique among mammalian proteinases because it is able to cleave the collagen molecule both inside and outside of the collagen helix (10). Deficiency of cathepsin K results in pyknodysostosis, an autosomal recessive osteochondrodysplasia (11). Expression of cathepsin K has been demonstrated in sev-eral chronic inflammatory lesions associated with bone destruction such as osteomyelitis (12), rheumatoid arthritis (13), osteoarthritis (14), nodular tenosynovitis (15), and aseptic hip prosthesis loosening (16).…”

Glycosaminoglycan-Mediated Loss of Cathepsin K Collagenolytic Activity in MPS I Contributes to Osteoclast and Growth Plate Abnormalities

“…3 The lack of functioning enzyme results in a condition known as pycnodysostosis in humans. 4 Osteoclasts are not able to degrade the organic matrix and so undegraded collagen accumulates in the resorption lacuna and in cellular lysosomes. 5 Patients with pycnodysostosis typically have decreased bone resorption accompanied by enhanced bone density and are dwarfs.…”

An atypical subtrochanteric femoral fracture from pycnodysostosis: A lesson from nature

“…(3)(4)(5) Cathepsin K is a lysosomal cysteine protease highly expressed in osteoclasts alone, thereby restricting the phenotype of pycnodysostosis to bone. (6) The treatment of pycnodysostosis is restricted to symptomatic management of fractures and other skeletal problems, but insights provided by identification of underlying gene mutations have led to the development of cathepsin K inhibitors for the treatment of osteoporosis. Although none are currently marketed, studies of three cathepsin K inhibitors have been reported (ie, relacatib, balicatib, and odanacatib).…”