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

(GAG) predominantly expressed in bone and cartilage, is required to promote its collagenolytic activity by
[18]
forming high molecular complexes . The formation of an active complex between the negatively charged
C4-S and specific positively charged residues of CatK (and shaping a so-called exosite, which is located
opposite the active site) is unique among human cysteine cathepsins [Figure 1]. In the absence of GAG, the
ability of CatK to cleave triple helical collagen fibrils is impaired. Accordingly, it has been hypothesized that
selective inhibitors able to disrupt CatK/C4-S complex by targeting the C4-S binding exosite could inhibit
its collagenase activity without impairing other regulatory peptidase and protease activities (see further
section). In addition to collagens, CatK hydrolyzes other extracellular matrix (ECM) components such as
elastin fibers, and aggrecans . CatK is a lysosomal protease that is mainly active at acidic pH 5.5 and
[19]
rapidly inactivated at neutral pH. Nevertheless, lung macrophages and osteoclasts secrete CatK, which
remains active in the pericellular space due to the presence of H -ATPase pump or Na /H exchanger [20,21] . In
+
+
+
addition to its primary location in bones, high levels of CatK were also detected in synovial fibroblasts,
aortic smooth muscle cells, macrophages, and epithelial cells, while CatK mRNA levels were increased in
other tissues such as ovary, synovia, heart, skin, and lungs, following scarring or inflammation [10,22,23] . In
addition to its collagenolytic activity and its involvement in ECM remodeling, CatK takes part in the
maturation of thyroid hormones, participating in the processing of thyroglobulin [24,25] . Moreover, CatK plays
a pivotal protective role in lung homeostasis via its ability to proteolytically inactivate TGF-β1 [26,27] . In the
last decade, a paradigm shift from the concept of “simple” protein-degrading enzymes to key signaling
scissors was proposed , as demonstrated by the paramount importance of cysteine cathepsins (including
[28]
CatK) in diverse cell signaling cascades (e.g., PPAR-γ/caspase-8-mediated cell apoptosis, TGF-β signaling
pathway) [29-33] .

Cathepsin K in osteoporosis, bone cancer and oral diseases
Besides its biological roles in bone turnover, skeletal, heart, lung and intestinal development, and
reproduction, CatK expression may be dysregulated in bone resorption disorders like osteoporosis and bone
metastasis . CatK has been identified as the main osteoclastic bone-resorbing protease and its
[5]
overexpression is markedly related to extensive bone loss, which is highlighted by the presence of N-
telopeptide (NTx) collagen fragments (a typical product of CatK cleavage) in the urine/serum of
[6]
osteoporotic patients . Since inhibition of CatK active site could prevent bone resorption without
perturbing bone formation, the protease has become an attractive and validated target for anti-resorptive
[34]
drug development . Moreover, abnormally high expression of CatK in various organs intertwines with the
massive hydrolysis of elastin fibers or collagens in numerous cancers such as prostate, breast, lung, and bone
cancers [8,10] . CatK, which contributes to tumor progression via extracellular degradation of ECM proteins,
cytokines inactivation/activation or pro-matrix metalloproteinases processing, was proposed for differential
prognostic purposes.

Oral and maxillofacial abnormalities were found in Ctsk(-/-) mice. Similarly, close relationships between
defective CatK and oral diseases were identified in patients with pycnodysostosis , but also in patients with
[35]
periodontitis, peri-implantitis, tooth movement, oral and maxillofacial tumor, root resorption, and
[36]
periapical disease (see for review: ). Extensive histological and ultrastructural changes of cementum, a part
of the periodontium, were observed, which might be linked to compromised proteolytic activity of CatK .
[37]
Otherwise, mutations of human CLCN7, which encodes voltage-gated chloride channel 7 (so-called ClC-7),
lead to osteopetrosis, associated with deformities in craniofacial morphology and marked tooth dysplasia.
Also, loss of CLCN7 function resulted in lysosomal storage in the brain as well as in the jaw and its
surrounding, which has been associated with CatK downregulation .
[38]