Cysteine peptidases (CPs) are phylogenetically ubiquitous enzymes that can be classified into clans of evolutionarily independent proteins based on the structural organization of the active site. In mammals, two of the major clans represented in the genome are: the CA clan, whose members share a structure and evolutionary history with papain; and the CD clan, which includes the legumains and caspases. This review focuses on the properties of these enzymes, with an emphasis on their potential roles in the oral cavity. The human genome encodes at least (but possibly no more than) 11 distinct enzymes, called cathepsins, that are members of the papain family C1A. Ten of these are present in rodents, which also carry additional genes encoding other cathepsins and cathepsin-like proteins. Human cathepsins are best known from the ubiquitously expressed lysosomal cathepsins B, H, and L, and dipeptidyl peptidase I (DPP I), which until recently were considered to mediate primarily “housekeeping” functions in the ce...

https://journals.sagepub.com/doi/pdf/10.1177/154411130201300304

Cysteine peptidases of mammals: their biological roles and potential effects in the oral cavity and other tissues in health and disease

Involvement of cystatin C in immunity and apoptosis

The correlation of RANK, RANKL and TNFα expression with bone loss volume and polyethylene wear debris around hip implants

Objectives: To study the expression of cysteine proteinases, particularly cathepsin K, and their extracellular inhibitor cystatin C in articular cartilage of transgenic Del1 mice which harbour a short deletion mutation in a type II collagen transgene and are predisposed to early onset osteoarthritis. 

Methods: Northern analysis was used to measure mRNA levels of cathepsins B, H, K, L, and S, and cystatin C in total RNA extracted from knee joints of Del1 mice, using their non-transgenic litter mates as controls. Immunohistochemistry and morphometry was used to study the distribution of cathepsin K and cystatin C in the knee joints. 

Results: Up regulation of cathepsin K mRNA expression was seen in the knee joints of transgenic Del1 mice at the onset of cartilage degeneration. Cathepsin K was found near sites of matrix destruction in articular chondrocytes, particularly in clusters of proliferating cells, and in calcified cartilaginous matrix. In intact articular cartilage of control animals, cathepsin K was only seen in a small number of chondrocytes. Upon aging, control animals also developed osteoarthritis, which was accompanied by increased cathepsin K expression. Cystatin C was mostly localised in and around chondrocytes located in calcified cartilage, with no obvious association with the onset of cartilage degeneration. 

Conclusion: The temporospatial distribution of cathepsin K in osteoarthritic cartilage suggests a role for this enzyme in the pathogenesis of osteoarthritis. Because cathepsin K can digest cartilage matrix components it may contribute to the development of osteoarthritic lesions. These data may provide new clues for the development of treatments aimed at preventing cartilage degeneration.

https://ard.bmj.com/content/annrheumdis/63/6/649.full.pdf

Up regulation of cathepsin K expression in articular chondrocytes in a transgenic mouse model for osteoarthritis

Journal of Pharmaceutical and Biological Sciences (An international peer-reviewed Bi-monthly journal) is a peer-reviewed journal of high quality devoted to provide a platform to scientists and researchers all over the world, for the dissemination of knowledge in the field of Pharmaceutical, Biological and other allied sciences. The journal policy is to publish work deemed by peer reviewers to be a coherent and sound addition to scientific knowledge and to put less emphasis on interest levels, provided that the research constitutes a useful contribution to the field. The Journal publishes original research papers, review articles, and short communications in all aspects of Pharmacy, Biology and other allied sciences.

Journal of Pharmaceutical and Biomedical Sciences

OBJECTIVE: To investigate the expression of the bone matrix degrading cysteine proteinase cathepsin K and to determine the colocalization of cathepsin K with polyethylene (PE) particles in tissue specimens of patients with aseptic hip prosthesis loosening (AHPL). METHODS: The expression of cathepsin K was studied by immunohistochemistry in tissue specimens of 9 patients with aseptically loosened acetabular components of failed cementless total hip replacements. The expression of cathepsin K was compared to that of the macrophage marker CD68 by serial section analysis. Double labeling of the expression of cathepsin K or CD68 by immunohistochemistry and of PE particles by modified Oil Red staining method was performed. RESULTS: Cathepsin K could be predominantly detected in osteoclasts attached to the bone tissue, while only a few (CD68+) mononuclear and multinucleated foreign body giant cells (MGC) were positive for this enzyme. By double labeling with Oil Red staining we found the majority of CD68 positive cells of the periprosthetic tissue that were colocalized with PE particles. However, cathepsin K-expressing osteoclasts could not be stained with Oil Red. CONCLUSION: The present data suggest that in AHPL neither mononuclear cells nor MGC but rather osteoclasts are mainly involved in cathepsin K mediated bone matrix destruction. Using double labeling of immunohistochemistry and Oil Red staining we observed that the cathepsin K-expressing osteoclasts did not include PE particles.

https://www.jrheum.org/content/jrheum/28/7/1615.full.pdf

Cathepsin K in aseptic hip prosthesis loosening: expression in osteoclasts without polyethylene wear particles.

AIMS The main complication in total hip arthroplasty is aseptic loosening. Wear-induced inflammatory processes lead to periprosthetic granulation tissue, which induces bone degradation due to aseptic osteolysis. At the site of bone degradation,the cell populations have not been further analysed so far. Therefore, the present study was designed to analyse bone degradation tissue in comparison to periprosthetic granulation tissue. METHODS Tissue specimens of 14 patients with failed modular cup components of cementless total hip arthroplasties were obtained during revision surgery. Immunohistochemistry was performed by using anti-CD 31 (endothelial cells),anti-CD 45 (granulocytes and lymphocytes) and anti-CD 68 antibodies (mononuclear phagocyte system, MPS). Fibroblasts and osteoblasts were immunohistochemically distinguished as CD 31/45/68-negative cells. Semiquantitative analyses,including a morphometric study, were then performed both in the bone degradation zone and in the periprosthetic granulation tissue. RESULTS At the site of bone degradation, the majority of cells belonged to MPS (73.6 +/- 3.31%),while fibroblasts were significantly less frequent (9.6 +/-1.67%). A distinct population of endothelial cells (7.75+/- 1.4%) as well as lymphoplasmacellular cells (5.75+/-2.35%) were observed. In addition,only a small amount of neutrophilic granulocytes (0.7 +/- 0.4 %) were detected. In the periprosthetic granulation tissue, findings were very similar to those of the bone degradation zone,with the exception of higher amounts of fibroblasts (15.69 +/- 2.74%). CONCLUSIONS This study confirms that, in aseptic hip arthroplasty loosening, the majority of cells detected at the site of bone degradation are of the MPS, which are predominantly involved in osteolytic processes. There is no pathologically significant difference between the cell population of periprosthetic granulation tissue and granulation tissue at the sites of bone degradation.

Immunhistochemische Analyse periprothetischer Osteolysen aseptischer Hüftprothesenlockerungen

Aim The long-term results of rheumatoid arthritis are unsatisfactory despite the mono or combination therapy of conventional "disease-modifying antirheumatic drugs". Therefore in the recent past the administration of a combination of Methotrexate with Leflunomide takes place more frequently. To what extent the perioperative infection rate is influenced by the individual immune-modulating drugs, is still disputed and should quantified on the basis the rheumatism orthopaedic patient collective of an orthopaedic university clinic. Method The clinical progresses of patients after operative treatment in the orthopaedic hospital, since introduction of the Leflunomide, were evaluated with regard to perioperative infection. Results Of 16 patients, who were observed during a period of 1,5 years under a combination therapy by MTX/Leflunomide, three exhibited a heavy infection of the musculoskeletal system. Conclusion The combination of the two above mentioned drugs affects different pathophysiological processes. Synergistic effects in therapy but also with regard to side effects must be expected. First available reports on this combination therapy do not refer to a increased infection/risk. The observation of three serious infections under the combination MTX/Leflunomide prompted us to call attention to this risk. In particular with infection-susceptible bone-surgical operations such a combination of immune-modulating medicines should be employed with caution. The recent literature is discussed.

Infections of the musculoskeletal system with chronic polyarthritis during a combination therapy with Methotrexate and Leflunomide

Objective. To compare the expression of cathepsin B and its endogenous inhibitor cystatin C in synovial tissue of patients with rheumatoid arthritis (RA) and to determine the cell type expressing cystatin C. Methods. The expression of cathepsin B and cystatin C was studied by immunohistochemistry in synovial tissue of 10 patients with RA and compared to healthy controls. Applying double labeling methods, the expression of cathepsin B was compared to that of cystatin C. To determine the cell type expressing cystatin C, double labeling with anti-CD68 (PG-M1) was performed. Results. Both cystatin C and cathepsin B were strongly expressed in synoviocytes of patients with RA. Furthermore, fibroproliferative tissue at the site of cartilage and bone destruction contained fibroblast-like and macrophage-like cells positive for cystatin C and cathepsin B, whereas normal synovial tissue exhibited only limited expression of these molecules. Osteoclasts revealed positive staining for CD68 and cystatin C, but not for cathepsin B. Conclusion. Cystatin C is a product of both macrophage-like and fibroblast-like synoviocytes. The strong expression of both the matrix degrading cysteine proteinase cathepsin B and the cysteine proteinase inhibitor cystatin C in rheumatoid synovium, particularly at the sites of bone and cartilage erosion, suggests that cystatin C - although increased - is not sufficient to prevent matrix degradation by cathepsin B.

Cathepsin B and its endogenous inhibitor cystatin C in rheumatoid arthritis synovium.

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Cathepsin K in aseptic hip prosthesis loosening: expression in osteoclasts without polyethylene wear particles.

Immunhistochemische Analyse periprothetischer Osteolysen aseptischer Hüftprothesenlockerungen

Infections of the musculoskeletal system with chronic polyarthritis during a combination therapy with Methotrexate and Leflunomide

Cathepsin B and its endogenous inhibitor cystatin C in rheumatoid arthritis synovium.