An update on bisphosphonates

Cohen, Stanley

doi:10.1007/s11926-004-0084-2

Cited by 25 publications

(9 citation statements)

References 43 publications

(31 reference statements)

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“…Examples of critical medical importance include systemic amyloidoses, neurodegenerative diseases, and prion-related encephalopathies (57,58). In such pathological processes proteins lose their native structures and undergo cross-␤ assembly to form fibrils (59,60).…”

Section: Discussionmentioning

confidence: 99%

Proinsulin Is Refractory to Protein Fibrillation

Huang

Dong

Phillips

et al. 2005

Journal of Biological Chemistry

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Insulin is susceptible to fibrillation, a misfolding process leading to well ordered cross-␤ assembly. Protection from fibrillation in ␤ cells is provided by sequestration of the susceptible monomer within zinc hexamers. We demonstrate that proinsulin is refractory to fibrillation under conditions that promote the rapid fibrillation of zinc-free insulin. Proinsulin fibrils, as probed by Raman microscopy, are nonetheless similar in structure to insulin fibrils. The connecting peptide, although not well ordered in native proinsulin, participates in a fibril-specific ␤-sheet. Native insulin and proinsulin exhibit similar free energies of unfolding as inferred from guanidine denaturation studies: relative amyloidogenicities are thus not correlated with global stability. Strikingly, the susceptibility of proinsulin to fibrillation is increased by scission of the connecting peptide at single sites. We thus propose that the connecting peptide constrains a large scale conformational change in the misfolded protein. A tethering mechanism is proposed based on a model of an insulin protofilament derived from electron-microscopic image reconstruction. The proposed relationship between cross-␤ assembly and protein topology is supported by studies of single-chain analogs (mini-proinsulin and insulin-like growth factor I) in which foreshortened connecting peptides further retard fibrillation. In addition to its classic function to facilitate disulfide pairing, the connecting peptide may protect ␤ cells from toxic protein misfolding in the endoplasmic reticulum.

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Section: Discussionmentioning

confidence: 99%

Proinsulin Is Refractory to Protein Fibrillation

Huang

Dong

Phillips

et al. 2005

Journal of Biological Chemistry

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“…Increased osteoclast activity and bone turnover rate are known pathological characteristics of subchondral bone in OA, particularly at early stage. For this reason, the common anti-resorptive medicine, bisphosphonate, has been tested its efficacy for treating OA in many clinical trials 134 . Though the outcome in human subjects was not as encouraging as in animal OA models 135–139 , specific drugs within the bisphosphonate class did show benefit effects in a few human studies.…”

Section: Modulation Of Tgfβ Activity In Subchondral Bone As a Potentimentioning

confidence: 99%

Targeting TGFβ signaling in subchondral bone and articular cartilage homeostasis

Zhen

Cao

2014

Trends in Pharmacological Sciences

183

145

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Osteoarthritis (OA) is the most common degenerative joint disease, and there is no disease-modifying therapy for OA currently available. Targeting of articular cartilage alone may not be sufficient to halt this disease progression. Articular cartilage and subchondral bone act as a functional unit. Increasing evidence indicates that transforming growth factor β (TGFβ) plays a crucial role in maintaining homeostasis of both articular cartilage and subchondral bone. Activation of extracellular matrix latent TGFβ at the appropriate time and location is the prerequisite for its function. Aberrant activation of TGFβ in the subchondral bone in response to abnormal mechanical loading environment induces formation of osteroid islets at onset of osteoarthritis. As a result, alteration of subchondral bone structure changes the stress distribution on the articular cartilage and leads to its degeneration. Thus, inhibition of TGFβ activity in the subchondral bone may provide a new avenue of treatment for OA. In this review, we will respectively discuss the role of TGFβ in homeostasis of articular cartilage and subchondral bone as a novel target for OA therapy.

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“…Bisphosphonates are a class of synthetic analogs of pyrophosphate, which have been widely used for treatment of different diseases characterized by intense bone resorption, such as Paget's disease, osteoporosis, multiple myeloma, bone metastases of breast and prostate tumors (1)(2)(3). These drugs inhibit bone resorption mainly by inhibiting osteoclast differentiation and activity (4).…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic Effects of Zoledronic Acid on Human Epithelial Cells and Gingival Fibroblasts

Basso¹,

Pansani

Oliveira

et al. 2013

Braz. Dent. J.

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Bisphosphonate-induced osteonecrosis has been related to the cytotoxicity of these drugs on oral mucosa cells. A previous study showed that 5 µM of zoledronic acid (ZA), a nitrogen-containing bisphosphonate, is the highest concentration of this drug found in the oral cavity of patients under treatment. Therefore, in order to simulate an osteonecrosis clinical condition, the aim of this study was to evaluate the highest concentration of ZA applied on human epithelial cells (HaCaT) and gingival fibroblasts. For this purpose, cells (3 × 10(4) cells/cm2) were seeded in wells for 48 h using complete culture medium (cDMEM). After 48 h incubation, the cDMEM was replaced by fresh serum-free culture medium (DMEM-FBS) in which the cells were maintained for additional 24 h. Then, 5 µM ZA were added to the DMEM-FBS and the cells incubated in contact with the drug for 48 h. After this period, the number of viable cells (trypan blue), cell viability (MTT assay), total protein (TP) production and cell morphology (SEM analysis) were assessed. Data were analyzed statistically by Mann-Whitney, ANOVA and Tukey's test (α=0.05). ZA caused a significant reduction in the number of viable cells and decreased the metabolic activity of both cell lines. However, decrease of TP production occurred only in the epithelial cell cultures. Morphological alterations were observed in both cell types treated with ZA. In conclusion, ZA (5 µM) was cytotoxic to human epithelial cells and gingival fibroblast cultures, which could be associated, clinically, with the development of bisphosphonate-induced osteonecrosis.

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An update on bisphosphonates

Cited by 25 publications

References 43 publications

Proinsulin Is Refractory to Protein Fibrillation

Proinsulin Is Refractory to Protein Fibrillation

Targeting TGFβ signaling in subchondral bone and articular cartilage homeostasis

Cytotoxic Effects of Zoledronic Acid on Human Epithelial Cells and Gingival Fibroblasts

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