Participation of cathepsin L on bone resorption

Kakegawa, Hisao; Nikawa, Takeshi; Tagami, Kahori; Kamioka, Hiroshi; Sumitani, Koji; Kawata, Tomio; Drobnič‐Košorok, M.; Lenarčič, Brigita; Türk, Vito; Katunuma, Nobuhiko

doi:10.1016/0014-5793(93)80118-e

Cited by 120 publications

(63 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The soluble fraction was removed and co-incubated with 20 M N-CBZ-Phe-Arg-7-amido-4-methylcoumarin (Sigma), a substrate for cathepsins B and L, at 37°C for 10 min. To determine the specific contributions of the two proteases, other tubes were supplemented with 0.75 M CA-074 (Peptides International, Louisville, KY), a specific inhibitor of cathepsin B (Kakegawa et al, 1993;Inubushi et al, 1994). The activity of cathepsin L, determined as the fraction insensitive to CA-074, was completely suppressed when 0.25 M chymostatin (Sigma) was added to the assay.…”

Section: Methodsmentioning

confidence: 99%

Suppression of Cathepsins B and L Causes a Proliferation of Lysosomes and the Formation of Meganeurites in Hippocampus

Bednarski¹,

Ribak

Lynch³

1997

J. Neurosci.

View full text Add to dashboard Cite

Cultured hippocampal slices exhibited prominent ultrastructural features of brain aging after exposure to an inhibitor of cathepsins B and L. Six days of treatment with N-CBZ-Lphenylalanyl-L-alanine-diazomethylketone (ZPAD) resulted in a dramatic increase in the number of lysosomes in the perikarya of neurons and glial cells throughout the slices. Furthermore, lysosomes in CA1 and CA3 pyramidal cells were not restricted to the soma but instead were located throughout dendritic processes. Clusters of lysosomes were commonly found within bulging segments of proximal dendrites that were notable for an absence of microtubules and neurofilaments. Although pyknotic nuclei were sometimes encountered, most of the cells in slices exposed to ZPAD for 6 d appeared relatively normal. Slices given 7 d of recovery contained several unique features, compared with those processed immediately after incubation with the inhibitor. Cell bodies of CA1 neurons were largely cleared of the excess lysosomes but had gained fusiform, somatic extensions that were filled with fused lysosomes and related complex, dense bodies. These appendages, similar in form and content to structures previously referred to as "meganeurites," were not observed in CA3 neurons or granule cells. Because meganeurites were often interposed between cell body and axon, they have the potential to interfere with processes requiring axonal transport. It is suggested that inactivation of cathepsins B and L results in a proliferation of lysosomes and that meganeurite generation provides a means of storing residual catabolic organelles. The accumulated material could be eliminated by pinching off the meganeurite but, at least in some cases, this action would result in axotomy. Reduced cathepsin L activity, increased numbers of lysosomes, and the formation of meganeurites are all reported to occur during brain aging; thus, it is possible that the infusion of ZPAD into cultured slices sets in motion a greatly accelerated gerontological sequence.

show abstract

Section: Methodsmentioning

confidence: 99%

Suppression of Cathepsins B and L Causes a Proliferation of Lysosomes and the Formation of Meganeurites in Hippocampus

Bednarski¹,

Ribak

Lynch³

1997

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Pathologic cells may also secrete large amounts of cathepsin L, as observed in cultures of malignantly transformed cells (12). Of particular interest is the evidence of cathepsin L secretion at sites of normal bone resorption (13)(14)(15)(16), as well as elevated levels of cathepsin L in the synovial fluid of RA patients (17).…”

mentioning

confidence: 99%

Macrophage cathepsin L, a factor in the erosion of subchondral bone in rheumatoid arthritis

Iwata

Mort

Tateishi

et al. 1997

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To test the hypothesis that the proteinase cathepsin L is involved in the subchondral bone lesions found in chronic rheumatoid arthritis (RA).Methods. The medial tibia1 plateaus from 4 control cases and 30 patients diagnosed as having end-stage RA were examined immunochemically for cathepsin L.Results. RG lesions include large groups of mononuclear cells, many of which are rich in cathepsin L. Since these mononuclear cells contained the CD68 glycoprotein and, in the electron microscope, displayed an irregular cell surface, cytoplasmic vacuoles, lysosomes, and phagosomes, they were identified as belonging to the macrophage family. The lesions were classified into 2 main patterns, both displaying these cathepsin Grich cells, which, in at least 1 of the 2, were closely associated with bone degradation.Conclusion. The cathepsin L-rich macrophages are sufficiently numerous to be considered a major factor in producing the erosion of subchondral bone found in chronic RA lesions.Little is known of the cells involved in the resorption of subchondral bone that occurs in rheumatoid arthritis (RA), although there is some evidence that osteoclasts are responsible (1-3). There is general agreement that in healthy people, the degradation of bone is effected by osteoclasts through the secretion of cathepsin L and other proteinases into the acid-rich space that separates them from the bone (43). On the assumption Submitted for publication May 1, 1996; accepted in revised form September 30, 1996. that the same mechanism is operative in RA lesions, the expectation was that cathepsin L-producing osteoclasts would be observed in these lesions.In support of the potential role of cathepsin L in the resorption of bone and cartilage observed in RA patients, it is known that this enzyme degrades several bone components in vitro, namely, type I collagen (6) and the proteins osteonectin and osteocalcin (7), as well as components of cartilage, namely, type 11, IX, and XI collagens (6), the major proteoglycan, aggrecan (8), and link protein (9). Moreover, cathepsin L can be secreted outside the cell, as occurs in the course of antigen presentation (10) and in sperm maturation (11). Pathologic cells may also secrete large amounts of cathepsin L, as observed in cultures of malignantly transformed cells (12). Of particular interest is the evidence of cathepsin L secretion at sites of normal bone resorption (13-16), as well as elevated levels of cathepsin L in the synovial fluid of RA patients (17).The postulated role of osteoclasts in the production of RA lesions (1-3) implies that these cells synthesize and secrete cathepsin L and other proteinases for bone degradation. To find out whether osteoclasts or other cells are involved in the production of cathepsin L, we used an immunohistochemical approach. It was known that cathepsin L is synthesized as the 41-kd proteolytically inactive precursor procathepsin L, which in the acidic environment of the lysosome, gives rise to active forms of cathepsin L (18). We used an antibody raise...

show abstract

“…Vaes et al have shown that several inhibitors of cysteine proteinases, such as leupeptin, antipain, tosyl-lysyl chloromethane (TosLys-CH,Cl), benzyloxycarbonyl-phenylalanyl-alanyl-diazomethane (Z-Phe-Ala-CHN,) and E-64, markedly inhibited PTH-induced bone resorption in cultured mouse bone cells [4-61. Moreover, we reported that the bone pit formation induced by PTH was-strongly suppressed by PLCPI, a specific inhibitor of cathepsin L and/or L-like proteinase, and chymostatin, a selective inhibitor of cathepsin L, while no inhibition was observed by CA-074, a specific inhibitor of cathepsin B [13]. However, so far, there has been no apparent evidence that cathepsin L and/or L-like proteinase are secreted from the cells induced by PTH.…”

Section: Regulation Of Cysteine Proteinase Secretion By Pth and Calcimentioning

confidence: 99%

“…Rat osteoclasts were purified according to the method of Tezuka et al as described previously [13]. After purification, 90% of cells were multinucleate and had tartrate-resistant acid phosphatase activity.…”

Section: Cysteine Proteinase Activity In Rat Osteoclasts and Macrophagesmentioning

confidence: 99%

“…Kominami et al immunohistochernitally demonstrated the presence of cathepsin B and L in rat osteoclasts of the bone surface, suggesting the participation of these proteinases in the degradation of the organic constituents of the bone matrix [9]. We previously reported that rat osteoclastic bone resorption induced by parathyroid hormone (PTH) was markedly in- hibited by pig leucocyte cysteine proteinase inhibitor (PLCPI) [IO,1 I], a specific inhibitor of cathepsin L, and by chymos~tin, a selective inhibitor of cathepsin L, but not by CA-074 1121, a specific inhibitor of cathepsin B [13]. These facts suggest that cathepsin L or L-like proteinase, including procathepsin L, is the main proteinase responsible for bone collagen degradation.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The mechanisms and regulation of procathepsin L secretion from osteoclasts in bone resorption

et al. 1994

Self Cite

View full text Add to dashboard Cite

The secretion mechanisms of cathepsin L from osteoclasts in the process of bone resorption were investigated. The increases in bone pit numbers formed take place by PTH addition in parallel with the increases of cathepsin L and/or L-like proteinase activities in the culture medium of bone cells, and these were suppressed by the addition of calcitonin. The Z-Phe-Arg-MCA hydrolysing activity increased in the medium through the effect of F'TH is considered to be a kind of procathepsin L by Western blotting analysis, and was suppressed by calcitonin addition. Furthermore, monensin inhibited not only the PTH-induced pit formation, but also cysteine proteinase activity in osteoclasts. Therefore, the procathepsin L excreted might be transferred from endothelial reticulum via Golgi and/or via lysosomes.

show abstract

Participation of cathepsin L on bone resorption

Cited by 120 publications

References 28 publications

Suppression of Cathepsins B and L Causes a Proliferation of Lysosomes and the Formation of Meganeurites in Hippocampus

Suppression of Cathepsins B and L Causes a Proliferation of Lysosomes and the Formation of Meganeurites in Hippocampus

Macrophage cathepsin L, a factor in the erosion of subchondral bone in rheumatoid arthritis

The mechanisms and regulation of procathepsin L secretion from osteoclasts in bone resorption

Contact Info

Product

Resources

About