Disease relevance of Ctsk

• CONCLUSION: The constitutive expression of Ctsk and Ctsl messenger RNA in normal middle ear mucosa supports a function in the maintenance of middle ear mucosa homeostasis, and their downregulation as an early event in acute otitis media may reflect a disruption in that function [1].
• The abundant expression of cathepsin K selectively in osteoclasts strongly suggests that it plays a specialized role in bone resorption [2].
• A representative cathepsin K inhibitor was shown to attenuate PTH-stimulated hypercalcemia in the TPTX rat model [3].
• Our results suggest that a cysteine protease inhibitor could improve suspension-induced osteopenia by inhibiting cathepsin K-like activity in bone; however, it needs several improvements in the effect as a clinical drug [4].

High impact information on Ctsk

• Proteolytic excision of a repressive loop domain in tartrate-resistant acid phosphatase by cathepsin K in osteoclasts [5].
• In addition, numerous mononucleated cathepsin K-positive osteoclast precursor cells emerged in the synovial membrane [6].
• We investigated the role of acidification in human osteoclastic resorption and life span in vitro using inhibitors of chloride channels (NS5818/NS3696), the proton pump (bafilomycin) and cathepsin K [7].
• In addition, ESTs for cathepsin K were absent or at low frequency in cDNA libraries from numerous other tissues and cells [2].
• Specific targeting of cathepsin K and the vacuolar H+-ATPase at the ruffled border is blocked by U18666A [8].

Chemical compound and disease context of Ctsk

• Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption both in vitro and in vivo [9].
• Together, these data indicate that the cathepsin K inhibitor, SB 331750, prevented bone resorption in vivo and this inhibition resulted in prevention of ovariectomy-induced loss in trabecular structure [10].
• Cathepsin K is a member of the papain superfamily of cysteine proteases and plays a pivotal role in osteoclast-mediated bone resorption [11].

Biological context of Ctsk

• The changes in Ctsb and Ctsk gene expression were sustained at 48 hours [1].
• RESULTS: Middle ear mucosa expression of a gene cluster encoding the lysosomal cysteine proteases, cathepsins B (Ctsb), L (Ctsl), and K (Ctsk), was modified after S pneumoniae challenge [1].
• Cocrystallization of the C-3 diastereomeric 3-amidotetrahydrofuran-4-one analogue 16 with cathepsin K showed the inhibitor to occupy the unprimed side of the active site with the 3S diastereomer preferred [12].
• Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors [13].
• The synthesis, in vitro activities, and pharmacokinetics of a series of azepanone-based inhibitors of the cysteine protease cathepsin K (EC 3.4.22.38) are described [14].

Anatomical context of Ctsk

• Expression and localization of cathepsin k in adult rat sertoli cells [15].
• As is also true of cathepsin L, cathepsin K mRNA was found to be expressed by Sertoli cells at specific stages of the cycle of the seminiferous epithelium, with maximal expression at stages VI-VII [15].
• CONCLUSIONS: These results suggest that cathepsin K may activate the ROS-generating activity of TRACP in transcytotic vesicles of resorbing osteoclasts, the ROS being targeted to finalize degradation of organic bone matrix components during their transcytosis [16].
• Osteoclasts resorb bone by secreting acid and lysosomal enzymes such as cathepsin K into an extracellular resorption lacuna between the cell membrane and bone surface [16].
• Reflecting the U18666A-mediated inhibition of late endosome/lysosome transport, the resorptive membrane is disrupted and contains a paucity of cathepsin K and the vacuolar H+-ATPase [8].

Associations of Ctsk with chemical compounds

• Epoxy succinate peptide derivatives, CLIK-066, 088, 112, 121, 148, 181, 185 and 187, are typical specific inhibitors for cathepsin L. Aldehyde derivatives CLIK-060 and CLIK-164 showed specific inhibition against cathepsin S and cathepsin K, respectively [17].
• Structure-based development of pyridoxal propionate derivatives as specific inhibitors of cathepsin K in vitro and in vivo [18].
• CLIK-166, in which the position 4 aldehyde of CLIK-071 is replaced by a vinyl radical and position 5 is additionally modified, showed cathepsin K-specific inhibition at 10(-5) M [18].
• New synthetic pyridoxal propionate derivatives, -162, -163, and -164, in which the methyl arm of position 6 of CLIK-071 was additionally modified, strongly inhibited cathepsin K and cathepsin S weakly, but other cathepsins were not inhibited [18].
• Starting from the high-throughput screening hit 1a, novel cathepsin K inhibitors have been developed based on a purine scaffold [19].

Other interactions of Ctsk

• Further, the results suggest that cathepsin K, in both its secreted and lysosomal forms, may play a role in the degradation of Sertoli cell residual bodies [15].
• MMP-13 may play an important role in degradation of type I collagen in bone matrix, acting in concert with cathepsin K and MMP-9 produced by osteoclasts [20].
• Quantitative real-time PCR showed that TNF-alpha, RANK and TRAP mRNA expression did not change significantly with time, and that IL-1beta and cathepsin K changed slightly compared with those in the synovium [21].
• Our results show the presence of vacuolar H+-ATPase, small GTPase rab7 as well as dense aggregates of F-actin at the peripheral ruffled border, where basolaterally endocytosed transferrin and cathepsin K are delivered [22].
• The proteases MMP-13, cathepsin K, and tartrate-resistant acid phosphatase (TRAP) have collagenolytic activity and have been shown in rat ligament tissues [23].

Analytical, diagnostic and therapeutic context of Ctsk

• Cathepsin K was not detected by in situ hybridization in a panel of other tissues [2].
• Osteoclasts were identified by cathepsin K immunohistochemistry at various time points after the onset of arthritis [6].
• Western blot of human osteoclastoma or fetal rat humerus demonstrated bands of 38 and 27 kDa, consistent with sizes predicted for pro- and mature cathepsin K [2].
• Molecular modeling studies predicted the higher energy axial orientation at C-4 of 20 when bound within the active site of cathepsin K, a feature subsequently confirmed by X-ray crystallography [14].
• Real time quantitative RT-PCR demonstrated high levels of cathepsin K mRNA in bone marrow cultures, paralleling the degree of osteoclastogenesis [24].

References