Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice

Säftig, Paul; Hunziker, Ernst B.; Wehmeyer, Olaf; Jones, S. J.; Boyde, A.; Rommerskirch, Winfried; Moritz, JÃ¶rg Detlev; Schu, Peter; Figura, Kurt Von

doi:10.1073/pnas.95.23.13453

Cited by 823 publications

(587 citation statements)

References 36 publications

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“…From these mice, we collected the tibia and femur to extract total RNA and used for Northern blot and RT -PCR analyses to detect the mRNA expression of RANKL and MMPs. It is well known that cathepsin K and TRAP are specifically expressed in osteoclasts (Minkin, 1982;Saftig et al, 1998). The expression of cathepsin K and TRAP was markedly elevated in the femur of mouse B and in the femur and tibia of mouse C, indicating that osteoclastic bone resorption was in progress in these bones ( Figure 2B).…”

Section: Expression Of Rankl and Mmps In Bone With Metastasismentioning

confidence: 88%

Role of RANKL-induced osteoclast formation and MMP-dependent matrix degradation in bone destruction by breast cancer metastasis

et al. 2003

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Bone metastasis of breast cancer induces severe osteolysis with increased bone resorption. Osteoclast differentiation regulated by the receptor activator of NF-kB ligand (RANKL) in osteoblasts and matrix degradation induced by matrix metalloproteinases (MMPs) are thought to be involved in the process of bone resorption. When nude mice were inoculated with human breast cancer cells, MDA-MB-231(MDA-231), numerous osteoclasts resorbed bone and the degradation of the bone matrix markedly progressed in the femur and tibia with metastasis of the MDA-231 tumour. The expression of RANKL, MMP-13 and membrane-type 1-MMP mRNA was markedly elevated in bone with metastasis. When MDA-231 cells were cocultured with mouse calvaria, MDA-231 markedly induced bone resorption measured by calcium release from the calvaria, and the expression of RANKL, MMP-2 and MMP-13 was elevated in the calvaria after the coculture. The separation of MDA-231 from the calvaria using filter insert showed decreased bone resorption, suggesting that cell-to-cell interaction is essential for cancer-induced bone resorption. Adding MDA-231 cells to bone marrow cultures markedly induced osteoclast formation, and the expression of RANKL in osteoblasts was enhanced by contact with the cell surface of MDA-231 cells. These results indicate that RANKL-induced osteoclast formation and MMP-dependent matrix degradation are associated with osteolysis because of bone metastasis of breast cancer.

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Section: Expression Of Rankl and Mmps In Bone With Metastasismentioning

confidence: 88%

Role of RANKL-induced osteoclast formation and MMP-dependent matrix degradation in bone destruction by breast cancer metastasis

et al. 2003

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“…In fact, in vitro and in vivo studies suggest that the 2 types of proteases, MMP-9 and cathepsin K, are involved in bone resorption mediated by osteoclasts, performing the collagen degradation in bone (Delaisse et al, 2003;Everts et al, 1992). Votta et al (1997) found reduced bone resorption, both in vitro and in vivo, using an inhibitor of cathepsin K. Moreover, cathepsin K-deficient mice showed significant osteopetrosis (Saftig et al, 1998;Gowen et al, 1999). In periodontal area, increased levels of cathepsin K Figure 4.…”

Section: Discussionmentioning

confidence: 99%

NOD2 Contributes to Porphyromonas gingivalis–induced Bone Resorption

et al. 2014

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The NOD-like receptors are cytoplasmic proteins that sense microbial by-products released by invasive bacteria. Although NOD1 and NOD2 are functionally expressed in cells from oral tissues and play a role triggering immune responses, the role of NOD2 receptor in the bone resorption and in the modulation of osteoclastogenesis is still unclear. We show that in an experimental model of periodontitis with Porphyromonas gingivalis W83, NOD2-/- mice showed lower bone resorption when compared to wild type. Quantitative polymerase chain reaction analysis revealed that wild-type infected mice showed an elevated RANKL/OPG ratio when compared to NOD2-/- infected mice. Moreover, the expression of 2 osteoclast activity markers—cathepsin K and matrix metalloproteinase 9—was significantly lower in gingival tissue from NOD2-/- infected mice compared to WT infected ones. The in vitro study reported an increase in the expression of the NOD2 receptor 24 hr after stimulation of hematopoietic bone marrow cells with M-CSF and RANKL. We also evaluated the effect of direct activation of NOD2 receptor on osteoclastogenesis, by the activation of this receptor in preosteoclasts culture, with different concentrations of muramyl dipeptide. The results show no difference in the number of TRAP-positive cells. Although it did not alter the osteoclasts differentiation, the activation of NOD2 receptor led to a significant increase of cathepsin K expression. We confirm that this enzyme was active, since the osteoclasts resorption capacity was enhanced by muramyl dipeptide stimulation, evaluated in osteoassay plate. These results show that the lack of NOD2 receptor impairs the bone resorption, suggesting that NOD2 receptor could contribute to the progression of bone resorption in experimental model of periodontitis. The stimulation of NOD2 by its agonist, muramyl dipeptide, did not affect osteoclastogenesis, but it does favor the bone resorption capacity identified by increased osteoclast activity.

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“…Cathepsin L-deficient mice present only with a reduction in CD4 ϩ T cells (13) and recurrent hair loss (14). In contrast, cathepsin K deficiency causes pyknodysostosis in mice and humans, consistent with its expression in osteoclasts and function in bone resorption (15,16). In addition, loss-of-function mutations in the human cathepsin C gene have been associated with PapillonLefèvre syndrome, an autosomal recessive palmoplantar keratosis with periodontopathia (17).…”

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confidence: 99%

Neuronal loss and brain atrophy in mice lacking cathepsins B and L

Felbor

Kessler²,

Mothes³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

303

217

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Cathepsins B and L are widely expressed cysteine proteases implicated in both intracellular proteolysis and extracellular matrix remodeling. However, specific roles remain to be validated in vivo. Here we show that combined deficiency of cathepsins B and L in mice is lethal during the second to fourth week of life. Cathepsin B ؊/؊ ͞L ؊/؊ mice reveal a degree of brain atrophy not previously seen in mice. This is because of massive apoptosis of select neurons in the cerebral cortex and the cerebellar Purkinje and granule cell layers. Neurodegeneration is accompanied by pronounced reactive astrocytosis and is preceded by an accumulation of ultrastructurally and biochemically unique lysosomal bodies in large cortical neurons and by axonal enlargements. Our data demonstrate a pivotal role for cathepsins B and L in maintenance of the central nervous system.

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Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice

Cited by 823 publications

References 36 publications

Role of RANKL-induced osteoclast formation and MMP-dependent matrix degradation in bone destruction by breast cancer metastasis

Role of RANKL-induced osteoclast formation and MMP-dependent matrix degradation in bone destruction by breast cancer metastasis

NOD2 Contributes to Porphyromonas gingivalis–induced Bone Resorption

Neuronal loss and brain atrophy in mice lacking cathepsins B and L

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