Osteoclastogenesis is decreased by cysteine proteinase inhibitors

Brage, Monica; Lie, Anita; Ransjö, Maria; Kasprzykowski, Franciszek; Kasprzykowska, Regina; Abrahamson, Magnus; Grubb, Anders; Lerner, Ulf H.

doi:10.1016/j.bone.2003.11.018

Cited by 47 publications

(32 citation statements)

References 61 publications

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“…These results are in agreement with those studies which highlight that PO and BPH patients present increased levels of IL-6 and that this phenomenon appears to be correlated with the specific involvement of this pleiotropic cytokine in the pathogenesis of these inflammatory diseases [1,19,25,26]. On the other hand, the altered levels of cystatin C observed in PO patients further support the hypothesis that this inhibitor appears to play an active role in bone remodeling processes [8,[27][28][29]. However, these observations and the results obtained by the ROC curve analysis seem to rule out that, at least in breast cancer, IL-6 and Cyst C may be of clinical usefulness as specific markers of metastatic bone disease.…”

Section: Discussionsupporting

confidence: 94%

“…These data further confirm and extent previous observations from other studies which show that the infusion of ZA to patients with metastatic breast cancer induces a not statistically significant increase of the circulating levels of IL-6 up to 7 days after drug administration [30]. On the other hand, as IL-6 and Cyst C have been shown to stimulate osteoblast production and differentiation and to inhibit osteoclastogenesis [2,3,8,[27][28][29] it is conceivable to speculate that the increased levels of these molecules induced by ZA in PCa patients with bone metastases may likely reflect an enhanced osteoblastic activity, which in PCa is predominant [31,32], elicited by the drug. This hypothesis is further corroborated by some in vitro studies which highlight that ZA stimulate the proliferation and differentiation of normal human osteoblasts [33].…”

Section: Discussionsupporting

confidence: 90%

“…The activity of IL-6 during bone remodeling processes appears to be regulated by several factors [1][2][3]. Interestingly, recent in vitro studies show that cystatin C (Cyst C), a natural occurring inhibitor of osteoclast cysteine proteinase Cathepsin K, modulates IL-6 activity during bone resorption by interfering with late steps of osteoclast differentiation [8,9]. Therefore, any dysregulation in the expression levels of IL-6 and/or Cyst C may affect the normal bone turnover and, eventually, may lead to the onset of a number of pathological conditions associated with an altered bone resorption including tumor-related bone disease [10].…”

Section: Introductionmentioning

confidence: 99%

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Serum interleukin-6 in patients with metastatic bone disease: correlation with cystatin C

et al. 2008

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The clinical significance of serum interleukin-6 (IL-6) and its correlation with cystatin C (Cyst C), an endogenous inhibitor of cysteine proteinase cathepsin K, was investigated by immunoassays in patients with bone metastasis from breast cancer (BCa) or prostate cancer (PCa). Additional studies were also performed in these patients to assess the effects of zoledronic acid (ZA) administration on the circulating levels of these molecules. Mean IL-6 and Cyst C serum concentrations were significantly increased in BCa patients and in patients with primary osteoporosis (PO) compared to healthy subjects (HS). However, Cyst C, but not IL-6, resulted significantly more elevated in BCa patients than in PO patients. Furthermore, in BCa patients no correlation was highlighted between IL-6 and Cyst C or between these molecules and some clinicobiological parameters of malignant progression. Mean IL-6 levels were also higher in PCa patients and in patients with benign prostatic hyperplasia (BPH) than in HS while Cyst C resulted significantly higher in PCa but not in BPH patients as compared to HS. In PCa patients, a positive correlation was highlighted between IL-6 and number of bone metastases or serum prostate-specific antigen but not with the Gleason score. Conversely, Cyst C levels did not correlate with any of the parameters considered above or with IL-6. Receiver operating characteristic (ROC) curve analysis showed a poor diagnostic accuracy of IL-6 and Cyst C to detect BCa patients with skeletal metastases while, in PCa patients, only IL-6 showed a fair diagnostic performance in this respect. Finally, the administration of ZA to patients with bone metastases induced a statistically significant increase of serum IL-6 and Cyst C only PCa patients with bone metastasis. These data indicate that IL-6 and Cyst C may be regarded as novel targets for cancer treatment and as markers of increased osteoblastic activity associated to bisphosphonate treatments in PCa patients with bone metastases.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Serum interleukin-6 in patients with metastatic bone disease: correlation with cystatin C

et al. 2008

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“…Bone biochemical markers support this interpretation. Resorption markers can respond quickly to changes in bone biology, because differentiation of osteoclasts occurs after just 4 d in vitro (11). Biomarkers of bone resorption, including NTx and C-telopeptide, have been observed in urine and serum after just 2 d of bed rest (12).…”

Section: Datamentioning

confidence: 99%

Rapidly assessing changes in bone mineral balance using natural stable calcium isotopes

Morgan

Skulan

Gordon

et al. 2012

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

121

104

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The ability to rapidly detect changes in bone mineral balance (BMB) would be of great value in the early diagnosis and evaluation of therapies for metabolic bone diseases such as osteoporosis and some cancers. However, measurements of BMB are hampered by difficulties with using biochemical markers to quantify the relative rates of bone resorption and formation and the need to wait months to years for altered BMB to produce changes in bone mineral density large enough to resolve by X-ray densitometry. We show here that, in humans, the natural abundances of Ca isotopes in urine change rapidly in response to changes in BMB. In a bed rest experiment, use of high-precision isotope ratio MS allowed the onset of bone loss to be detected in Ca isotope data after about 1 wk, long before bone mineral density has changed enough to be detectable with densitometry. The physiological basis of the relationship between Ca isotopes and BMB is sufficiently understood to allow quantitative translation of changes in Ca isotope abundances to changes in bone mineral density using a simple model. The rate of change of bone mineral density inferred from Ca isotopes is consistent with the rate observed by densitometry in long-term bed rest studies. Ca isotopic analysis provides a powerful way to monitor bone loss, potentially making it possible to diagnose metabolic bone disease and track the impact of treatments more effectively than is currently possible.osteopenia | biomarker | medical geology | biosignature | spaceflight

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“…The effect is exerted at a late stage of the osteoclast progenitor cell differentiation. The enzyme(s) and mechanisms involved is/are presently unknown (Brage et al, 2004).…”

Section: (2) Osteoclast Differentiationmentioning

confidence: 99%

New Molecules in the Tumor Necrosis Factor Ligand and Receptor Superfamilies with Importance for Physiological and Pathological Bone Resorption

Lerner

2004

Critical Reviews in Oral Biology & Medicine

132

105

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ABSTRACT:Osteoclasts are tissue-specific polykaryon bone-resorbing cells derived from the monocyte/macrophage hematopoietic lineage with specialized functions required for the adhesion of the cells to bone and the subsequent polarization of the cell membrane, secretion of acid to dissolve mineral crystals, and release of proteolytic enzymes to degrade the extracellular matrix proteins. Most pathological conditions in the skeleton lead to loss of bone due to excess osteoclastic bone resorption, including periodontal disease, rheumatoid arthritis, and osteoporosis. In rare cases, most of them genetic, patients with osteopetrosis exhibit sclerotic bone due either to a lack of osteoclasts or to non-functional osteoclasts. Mainly because of phenotypic findings in genetically manipulated mice or due to spontaneous mutations in humans, mice, and rats, several genes have been discovered as being crucial for osteoclast formation and activation. Recent breakthroughs in our understanding of osteoclast biology have revealed the critical roles in osteoclast differentiation played by RANKL, RANK, and OPG, three novel members of the tumor necrosis factor ligand and receptor superfamilies. The further study of these molecules and downstream signaling events are likely to provide a molecular basis for the development of new drugs for the treatment of diseases with excess or deficient osteoclastic bone resorption.

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Osteoclastogenesis is decreased by cysteine proteinase inhibitors

Cited by 47 publications

References 61 publications

Serum interleukin-6 in patients with metastatic bone disease: correlation with cystatin C

Serum interleukin-6 in patients with metastatic bone disease: correlation with cystatin C

Rapidly assessing changes in bone mineral balance using natural stable calcium isotopes

New Molecules in the Tumor Necrosis Factor Ligand and Receptor Superfamilies with Importance for Physiological and Pathological Bone Resorption

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