β2-Microglobulin stimulates osteoclast formation

Menaa, Cheikh; Esser, E.; Sprague, Stuart M.

doi:10.1038/ki.2008.100

Cited by 57 publications

(49 citation statements)

References 28 publications

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“…We have recently established that in the cell culture, oligomeric ␤2-m is cytotoxic, thus confirming previous data on the biological activity of soluble ␤2-m that is cytotoxic for certain cells (3) and mitogenic for other strains such as the osteoclasts (39). Because doxycycline deeply interferes with ␤2-m aggregation, we evaluated the effect of the drug on the biolog- ical activity of soluble and fibrillar ␤2-m. At equimolar concentrations, the presence of doxycycline fully abrogates the toxicity of soluble ␤2-m oligomers.…”

Section: Discussionsupporting

confidence: 51%

Effect of Tetracyclines on the Dynamics of Formation and Destructuration of β2-Microglobulin Amyloid Fibrils

Giorgetti

Raimondi

Pagano

et al. 2011

Journal of Biological Chemistry

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The discovery of methods suitable for the conversion in vitro of native proteins into amyloid fibrils has shed light on the molecular basis of amyloidosis and has provided fundamental tools for drug discovery. We have studied the capacity of a small library of tetracycline analogues to modulate the formation or destructuration of ␤2-microglobulin fibrils. The inhibition of fibrillogenesis of the wild type protein was first established in the presence of 20% trifluoroethanol and confirmed under a more physiologic environment including heparin and collagen. The latter conditions were also used to study the highly amyloidogenic variant, P32G. The NMR analysis showed that doxycycline inhibits ␤2-microglobulin self-association and stabilizes the native-like species through fast exchange interactions involving specific regions of the protein.Cell viability assays demonstrated that the drug abolishes the natural cytotoxic activity of soluble ␤2-microglobulin, further strengthening a possible in vivo therapeutic exploitation of this drug. Doxycycline can disassemble preformed fibrils, but the IC 50 is 5-fold higher than that necessary for the inhibition of fibrillogenesis. Fibril destructuration is a dynamic and timedependent process characterized by the early formation of cytotoxic protein aggregates that, in a few hours, convert into non-toxic insoluble material. The efficacy of doxycycline as a drug against dialysis-related amyloidosis would benefit from the ability of the drug to accumulate just in the skeletal system where amyloid is formed. In these tissues, the doxycycline concentration reaches values several folds higher than those resulting in inhibition of amyloidogenesis and amyloid destructuration in vitro.Amyloidosis associated with long term hemodialysis results from the deposition of full-length ␤2-microglobulin (␤2-m) 2 and its N-terminal truncated species ⌬N6␤2m in target tissues (1, 2). Although all peripheral organs (but not the brain) can be potentially affected (3), the muscle-skeletal tissues are the preferential target always involved in this type of amyloidosis. Despite significant progress achieved in the hemodialysis techniques, including the increased biocompatibility and the active removal of circulating ␤2-m, the onset of this amyloidosis can be delayed but not avoided in dialysis-related amyloidosis patients (4). New therapeutic approaches, targeting the process of protein aggregation and promoting fibril solubilization (5), are under investigation for the treatment of different types of amyloid diseases. Up until now, different classes of structurally unrelated compounds have been investigated for their ability to interfere with protein self-aggregation and to weaken the intermolecular interactions that stabilize the fibrillar structure of the aggregates (6). Over 10 years ago, iododoxorubicin was serendipitously discovered as the prototype of a class of compounds able to inhibit protein aggregation (7), but this compound was subsequently abandoned for its toxicity. The resemblance of the ...

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Section: Discussionsupporting

confidence: 51%

Effect of Tetracyclines on the Dynamics of Formation and Destructuration of β2-Microglobulin Amyloid Fibrils

Giorgetti

Raimondi

Pagano

et al. 2011

Journal of Biological Chemistry

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“…Nevertheless, from the bone perspective, these GCs could contribute to bone disease observed in CKD patients. A stimulation of osteoclastogenesis was demonstrated previously by Menaa et al [46] for ␤ 2 -microglobulin, supporting its involvement in bone resorption. The breakdown of the bone may result in a transfer of calcium from the bone to the blood, which may lead to vascular calcification.…”

Section: Contribution Of Guanidines To Uremic Toxicitysupporting

confidence: 53%

Guanidino Compounds as Cause of Cardiovascular Damage in Chronic Kidney Disease: An in vitro Evaluation

Schepers

Glorieux²,

Dou³

et al. 2010

Blood Purif

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Chronic kidney disease is considered a major cause of cardiovascular risk and non-traditional risk factors remain largely unknown. The in vitro toxicity of 10 guanidino compounds (GCs) was evaluated via a standardized approach on different cell systems of relevance in cardiovascular disease. The parameters evaluated were production of reactive oxygen species, expression of surface molecules, cell proliferation, cytotoxicity and calcification. Several GCs had a stimulatory effect on monocytes and granulocytes (SDMA, creatine and guanidinobutyric acid (GBA)). Some GCs (guandine (G), guanidinosuccinic acid (GSA) and SDMA) inhibited endothelial cell proliferation or reduced calcification in osteoblast-like human VSMC (ADMA, GSA and SDMA). Stimulation of osteoclastogenesis could be demonstrated for ADMA, G, guanidinoacetic acid and GBA in a RAW264.7 cell line. No compounds were cytotoxic to AoSMC or endothelial cells, nor influenced their viability. GCs, especially SDMA, likely contribute to cardiovascular complications in uremia, mainly those related to microinflammation and leukocyte activation.

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“…Dialysis Related Amyloidosis (DRA) is a pathological state afflicting patients suffering from kidney failure treated by long-term hemodialysis, related to inefficient b2m catabolism. 2,3 Under such pathological conditions the concentration of circulating b2m increases by a factor of 10-50, 2,4 leading to b2m…”

Section: Introductionmentioning

confidence: 99%

DE‐loop mutations affect β2 microglobulin stability, oligomerization, and the low‐pH unfolded form

et al. 2010

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b2 microglobulin (b2m) is the light chain of class-I major histocompatibility complex (MHC-I). Its accumulation in the blood of patients affected by kidney failure leads to amyloid deposition around skeletal joints and bones, a severe condition known as Dialysis Related Amyloidosis (DRA). In an effort to dissect the structural determinants of b2m aggregation, several b2m mutants have been previously studied. Among these, three single-residue mutations in the loop connecting strands D and E (W60G, W60V, D59P) have been shown to affect b2m amyloidogenic properties, and are here considered. To investigate the biochemical and biophysical properties of wild-type (w.t.) b2m and the three mutants, we explored thermal unfolding by Trp fluorescence and circular dichroism (CD). The W60G mutant reveals a pronounced increase in conformational stability. Protein oligomerization and reduction kinetics were investigated by electrospray-ionization mass spectrometry (ESI-MS). All the mutations analyzed here reduce the protein propensity to form soluble oligomers, suggesting a role for the DE-loop in intermolecular interactions. A partially folded intermediate, which may be involved in protein aggregation induced by acids, accumulates for all the tested proteins at pH 2.5 under oxidizing conditions. Moreover, the kinetics of disulfide reduction reveals specific differences among the tested mutants. Thus, b2m DE-loop mutations display long-range effects, affecting stability and structural properties of the native protein and its low-pH intermediate. The evidence presented here hints to a crucial role played by the DE-loop in determining the overall properties of native and partially folded b2m.

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β2-Microglobulin stimulates osteoclast formation

Cited by 57 publications

References 28 publications

Effect of Tetracyclines on the Dynamics of Formation and Destructuration of β2-Microglobulin Amyloid Fibrils

Effect of Tetracyclines on the Dynamics of Formation and Destructuration of β2-Microglobulin Amyloid Fibrils

Guanidino Compounds as Cause of Cardiovascular Damage in Chronic Kidney Disease: An in vitro Evaluation

DE‐loop mutations affect β2 microglobulin stability, oligomerization, and the low‐pH unfolded form

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