Myeloma Bone Disease: A Comprehensive Review.
therapies; multiple myeloma; bone disease
Multiple myeloma (MM) is a neoplastic clonal proliferation of plasma cells in the bone marrow microenvironment, characterized by overproduction of heavy- and light-chain monoclonal proteins (M-protein). These proteins are mainly found in the serum and/or urine. Reduction in normal gammaglobulins (immunoparesis) leads to an increased risk of infection. The primary site of origin is the bone marrow for nearly all patients affected by MM with disseminated marrow involvement in most cases. MM is known to involve bones and result in myeloma bone disease. Osteolytic lesions are seen in 80% of patients with MM which are complicated frequently by skeletal-related events (SRE) such as hypercalcemia, bone pain, pathological fractures, vertebral collapse, and spinal cord compression. These deteriorate the patient's quality of life and affect the overall survival of the patient. The underlying pathogenesis of myeloma bone disease involves uncoupling of the bone remodeling processes. Interaction of myeloma cells with the bone marrow microenvironment promotes the release of many biochemical markers including osteoclast activating factors and osteoblast inhibitory factors. Elevated levels of osteoclast activating factors such as RANK/RANKL/OPG, MIP-1-α., TNF-α, IL-3, IL-6, and IL-11 increase bone resorption by osteoclast stimulation, differentiation, and maturation, whereas osteoblast inhibitory factors such as the Wnt/DKK1 pathway, secreted frizzle related protein-2, and runt-related transcription factor 2 inhibit osteoblast differentiation and formation leading to decreased bone formation. These biochemical factors also help in development and utilization of appropriate anti-myeloma treatments in myeloma patients. This review article summarizes the pathophysiology and the recent developments of abnormal bone remodeling in MM, while reviewing various approved and potential treatments for myeloma bone disease.
Mukkamalla SKR; Malipeddi D
International Journal Of Molecular Sciences
2021
2021-06-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.3390/ijms22126208" target="_blank" rel="noreferrer noopener">10.3390/ijms22126208</a>
Leptin in Atherosclerosis: Focus on Macrophages, Endothelial and Smooth Muscle Cells.
Humans; atherosclerosis; Animals; endothelial cells; macrophages; vascular smooth muscle cells; Leptin/metabolism; Atherosclerosis/metabolism; Diabetes Mellitus/metabolism; Endothelial Cells/metabolism; hyperleptinemia; Macrophages/metabolism; Myocytes Smooth Muscle/metabolism; Obesity/metabolism; ADIPOSE tissue physiology; LEPTIN; LEPTIN receptors; MACROPHAGES; MUSCLE cells; SMOOTH muscle
Increasing adipose tissue mass in obesity directly correlates with elevated circulating leptin levels. Leptin is an adipokine known to play a role in numerous biological processes including regulation of energy homeostasis, inflammation, vascular function and angiogenesis. While physiological concentrations of leptin may exhibit multiple beneficial effects, chronically elevated pathophysiological levels or hyperleptinemia, characteristic of obesity and diabetes, is a major risk factor for development of atherosclerosis. Hyperleptinemia results in a state of selective leptin resistance such that while beneficial metabolic effects of leptin are dampened, deleterious vascular effects of leptin are conserved attributing to vascular dysfunction. Leptin exerts potent proatherogenic effects on multiple vascular cell types including macrophages, endothelial cells and smooth muscle cells; these effects are mediated via an interaction of leptin with the long form of leptin receptor, abundantly expressed in atherosclerotic plaques. This review provides a summary of recent in vivo and in vitro studies that highlight a role of leptin in the pathogenesis of atherosclerotic complications associated with obesity and diabetes.
Raman P; Khanal S
International Journal Of Molecular Sciences
2021
2021-05-21
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.3390/ijms22115446" target="_blank" rel="noreferrer noopener">10.3390/ijms22115446</a>
Early pro-inflammatory remodeling of HDL proteome in a model of diet-induced obesity: 2H2O-metabolic labeling-based kinetic approach.
inflammation; NAFLD; proteome dynamics; dyslipidemia; insulin resistance; diet-induced obesity; acute-phase proteins; high-density lipoprotein; high-fat diet
Mice fed a high-fat diet for 12 weeks or longer develop hyperglycemia, insulin resistance, dyslipidemia, and fatty liver. Additionally, a high-fat diet induces inflammation that remodels and affects the anti-inflammatory and antiatherogenic property of the high-density lipoprotein (HDL). However, the precise time course of metabolic disease progression and HDL remodeling remains unclear. Short-term (four weeks) high-fat feeding (60% fat calories) was performed in wild-type male C57BL/6J mice to gain insights into the early metabolic disease processes in conjunction with a HDL proteome dynamics analysis using a heavy water metabolic labeling approach. The high-fat diet-fed mice developed hyperglycemia, impaired glucose tolerance, hypercholesterolemia without hypertriglyceridemia or hepatic steatosis. A plasma HDL proteome dynamics analysis revealed increased turnover rates (and reduced half-lives) of several acute-phase response proteins involved in innate immunity, including complement C3 (12.77 ± 0.81 vs. 9.98 ± 1.20 h, p < 0.005), complement factor B (12.71 ± 1.01 vs. 10.85 ± 1.04 h, p < 0.05), complement Factor H (19.60 ± 1.84 vs. 16.80 ± 1.58 h, p < 0.05), and complement factor I (25.25 ± 1.29 vs. 19.88 ± 1.50 h, p < 0.005). Our findings suggest that an early immune response-induced inflammatory remodeling of the plasma HDL proteome precedes the diet-induced steatosis and dyslipidemia.
Sadana P;Lin Li;Aghayev M;Ilchenko S;Kasumov T
International Journal of Molecular Sciences
2020
2020-10-10
journalArticle
<a href="http://doi.org/10.3390/ijms21207472" target="_blank" rel="noreferrer noopener">10.3390/ijms21207472</a>
Ischemic heart disease pathophysiology paradigms overview: From plaque activation to microvascular dysfunction.
atherosclerosis; ion channels; microcirculation; myocardial infarction; coronary blood flow; ischemic heart disease
Ischemic heart disease still represents a large burden on individuals and health care resources worldwide. By conventions, it is equated with atherosclerotic plaque due to flow-limiting obstruction in large-medium sized coronary arteries. However, clinical, angiographic and autoptic findings suggest a multifaceted pathophysiology for ischemic heart disease and just some cases are caused by severe or complicated atherosclerotic plaques. Currently there is no well-defined assessment of ischemic heart disease pathophysiology that satisfies all the observations and sometimes the underlying mechanism to everyday ischemic heart disease ward cases is misleading. In order to better examine this complicated disease and to provide future perspectives, it is important to know and analyze the pathophysiological mechanisms that underline it, because ischemic heart disease is not always determined by atherosclerotic plaque complication. Therefore, in order to have a more complete comprehension of ischemic heart disease we propose an overview of the available pathophysiological paradigms, from plaque activation to microvascular dysfunction.
Severino P;D'Amato A;Pucci M;Infusino F;Adamo F;Birtolo LI;Netti L;Montefusco G;Chimenti C;Lavalle C;Maestrini V;Mancone M;Chilian WM;Fedele F
International Journal of Molecular Sciences
2020
2020-10-30
journalArticle
<a href="http://doi.org/10.3390/ijms21218118" target="_blank" rel="noreferrer noopener">10.3390/ijms21218118</a>
Small non-coding RNAome of ageing chondrocytes.
chondrocyte; ageing; equine; small non-coding RNA
Ageing is a leading risk factor predisposing cartilage to osteoarthritis. However, little research has been conducted on the effect of ageing on the expression of small non-coding RNAs (sncRNAs). RNA from young and old chondrocytes from macroscopically normal equine metacarpophalangeal joints was extracted and subjected to small RNA sequencing (RNA-seq). Differential expression analysis was performed in R using package DESeq2. For transfer RNA (tRNA) fragment analysis, tRNA reads were aligned to horse tRNA sequences using Bowtie2 version 2.2.5. Selected microRNA (miRNAs or miRs) and small nucleolar RNA (snoRNA) findings were validated using real-time quantitative Polymerase Chain Reaction (qRT-PCR) in an extended cohort of equine chondrocytes. tRNA fragments were further investigated in low- and high-grade OA human cartilage tissue. In total, 83 sncRNAs were differentially expressed between young and old equine chondrocytes, including miRNAs, snoRNAs, small nuclear RNAs (snRNAs), and tRNAs. qRT-PCR analysis confirmed findings. tRNA fragment analysis revealed that tRNA halves (tiRNAs), tiRNA-5035-GluCTC and tiRNA-5031-GluCTC-1 were reduced in both high grade OA human cartilage and old equine chondrocytes. For the first time, we have measured the effect of ageing on the expression of sncRNAs in equine chondrocytes. Changes were detected in a number of different sncRNA species. This study supports a role for sncRNAs in ageing cartilage and their potential involvement in age-related cartilage diseases.
Balaskas P; Green JA; Haqqi TM; Dyer P; Kharaz YA; Fang Y; Liu X; Welting TJM; Peffers MJ
International Journal of Molecular Sciences
2020
2020-08-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.3390/ijms21165675" target="_blank" rel="noreferrer noopener">10.3390/ijms21165675</a>
Trianthema portulacastrum Linn. displays anti-inflammatory responses during chemically induced rat mammary tumorigenesis through simultaneous and differential regulation of NF-kappaB and Nrf2 signaling pathways.
Female; Animals; Signal Transduction/*drug effects; Immunohistochemistry; Rats; Up-Regulation/drug effects; NF-kappa B/*metabolism; Aizoaceae/*chemistry/metabolism; Anti-Inflammatory Agents/chemistry/isolation & purification/*pharmacology; Breast Neoplasms/chemically induced/metabolism/pathology; Cyclooxygenase 2/metabolism; HSP90 Heat-Shock Proteins/metabolism; NF-E2-Related Factor 2/*metabolism; Plant Extracts/chemistry; Sprague-Dawley; 10-Dimethyl-1; 9; Plant Components; 2-benzanthracene/toxicity; Aerial/chemistry/metabolism
Trianthema portulacastrum, a medicinal and dietary plant, has gained substantial importance due to its various pharmacological properties, including anti-inflammatory and anticarcinogenic activities. We have recently reported that a characterized T. portulacastrum extract (TPE) affords a considerable chemoprevention of 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumorigenesis though the underlying mechanisms are not completely understood. The objective of this study was to investigate anti-inflammatory mechanisms of TPE during DMBA mammary carcinogenesis in rats by monitoring cyclooxygenase-2 (COX-2), heat shock protein 90 (HSP90), nuclear factor-kappaB (NF-kappaB) and nuclear factor erythroid 2-related factor 2 (Nrf2). Mammary tumors were harvested from our previous study in which TPE (50-200 mg/kg) was found to inhibit mammary tumorigenesis in a dose-response manner. The expressions of intratumor COX-2, HSP90, NF-kappaB, inhibitory kappaB-alpha (IkappaBalpha) and Nrf2 were determined by immunohistochemistry. TPE downregulated the expression of COX-2 and HSP90, blocked the degradation of IkappaBalpha, hampered the translocation of NF-kappaB from cytosol to nucleus and upregulated the expression and nuclear translocation of Nrf2 during DMBA mammary carcinogenesis. These results in conjunction with our previous findings suggest that TPE prevents DMBA-induced breast neoplasia by anti-inflammatory mechanisms mediated through simultaneous and differential modulation of two interconnected molecular circuits, namely NF-kappaB and Nrf2 signaling pathways.
Mandal Animesh; Bishayee Anupam
International journal of molecular sciences
2015
2015-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3390/ijms16022426" target="_blank" rel="noreferrer noopener">10.3390/ijms16022426</a>