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Page 2 of 11 Marchand-Adam et al. Rare Dis Orphan Drugs J 2023;2:3 https://dx.doi.org/10.20517/rdodj.2022.24

CATHEPSIN K: AN OVERVIEW
Introduction
Cysteine cathepsins (cathepsins B, C, F, H, K, L, O, S, V, X, and W) are a group of eleven structurally related
papain-like proteases (clan CA, family C1) in humans (MEROPS database; http://merops.sanger.ac.uk).
These enzymes are primarily found in acidic endosomal/lysosomal compartments where they partake in
various cellular processes (i.e. non-specific intracellular proteins degradation and turnover, autophagy, and
[1,2]
immune responses) . Cysteine cathepsins, which are expressed either ubiquitously or with tissue and cell-
type specificity, are also found outside lysosomes under specific conditions, contributing most often when
[3,4]
they are dysregulated to a wide range of pathophysiological events . Cathepsin K (CatK), which was
discovered in the 1990s, is a highly potent collagenase with a restricted cell distribution. Its predominant
expression in osteoclasts has promptly suggested specialized functions, including bone and articular
[5]
cartilage resorption . Moreover, CatK, which is overexpressed during osteoporosis as well in bone cancers,
was validated as an attractive target for anti-osteoporosis therapy and anti-tumor treatments [6-10] .
Meanwhile, CatK is gaining a growing interest according to potential other roles in physiological and
pathological processes, including rare diseases.

First, we will summarize contemporary knowledge on molecular aspects of CatK (genomic organization,
tissue expression, functional and structural characteristics, substrate specificity, regulation of its activity)
and review interventional strategies currently developed to selectively prevent the uncontrolled
collagenolytic activity of CatK in osteoporosis and bone cancer. Then, following a concise description of
lymphangioleiomyomatosis (LAM), a rare human disease, we will discuss both the interest in using CatK as
a new LAM biomarker and in targeting CatK for reducing lung destruction in LAM. Indeed, according to
the severity of the disease and the ensuing loss of lung function that might be associated with CatK
expression level in LAM, inhibition of CatK could be an additional therapeutic option, besides inhibition of
the mTOR (mammalian target of rapamycin) pathway.

Cathepsin K: molecular and biological characteristics
Human CatK is encoded by a single gene (CTSK, ~12.1 kb), localized on chromosome 1q21, like cathepsin S
[1]
(CatS) . CTSK gene expression is organized and tightly controlled at multiple steps, and likely involves the
interaction of several transcription factors that are activated by cytokines. For instance, interferon (IFN)-γ,
tumor necrosis factor (TNF)-α, interleukins (IL)-6 and -13 positively regulate the synthesis of CatK, while
transforming growth factor (TGF)-β1 and IL-10 may repress its expression level (for review: [5,11] ).

CatK (EC 3.4.22.38) is a monomeric endopeptidase (~24 kDa), which shares the common papain-like
structure, which consists of two globular domains folded together to give a ‘‘V’’-shaped active site cleft
configuration in the middle. Albeit the catalytic triad Cys , His , Asn (papain numbering) is well
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conserved, mapping studies of the crystal structure of CatK revealed differences in the substrate binding
subsites (labeled Sn-Sn’) that are located on both sides of the substrate’s scissile bond (corresponding to the
complementary positions Pn-Pn’) . Notably, residues forming the S2 binding pocket of CatK, its major
[12]
determinant of substrate specificity, are crucial for its prevalence for hydrophobic and aliphatic amino acids
(for review: ). Both binding pattern and substrate specificity of CatK were previously detailed by Lecaille
[5]
[5]
et al. . Importantly, CatK displays an unusual ability among cysteine cathepsins to accept Pro in the S2
pocket, a recognition residue of collagens. Based on these data, selective substrates and activity-based probes
of CatK were developed [13-16] .

Compared to other human proteases, CatK displays the unique potency to cleave within the triple helix of
type I and II collagens . Furthermore, the presence of chondroitin 4-sulfate (C4-S), a glycosaminoglycan
[17]