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Bone-targeted agents in multiple myeloma.

Osteolytic bone disease, characterized by bone pain, increased risk of pathologic fractures, tumor-induced hypercalcemia known as skeletal-related events (SREs), is a frequent complication of patients with multiple myeloma (MM) and persists even in the absence of active disease, resulting in a major cause of morbidity and mortality. The interaction between myeloma cells and their surrounding cells in the bone marrow (BM) microenvironment promotes both myeloma cell growth and bone destruction and forms the vicious cycle of MM bone disease. Therefore, therapeutic strategies targeting the interac

Organoids as Innovative Models for Bone and Joint Diseases.

Bone is one of the key components of the musculoskeletal system. Bone and joint disease are the fourth most widespread disease, in addition to cardiovascular disease, cancer, and diabetes, which seriously affect people's quality of life. Bone organoids seem to be a great model by which to promote the research method, which further could improve the treatment of bone and joint disease in the future. Here, we introduce the various bone and joint diseases and their biology, and the conditions of organoid culture, comparing the in vitro models among 2D, 3D, and organoids. We summarize the differin

Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders.

Very recently, heterozygous mutations in the genes encoding transforming growth factor beta receptors I (TGFBR1) and II (TGFBR2) have been reported in Loeys-Dietz aortic aneurysm syndrome (LDS). In addition, dominant TGFBR2 mutations have been identified in Marfan syndrome type 2 (MFS2) and familial thoracic aortic aneurysms and dissections (TAAD). In the past, mutations of these genes were associated with atherosclerosis and several human cancers. Here, we report a total of nine novel and one known heterozygous sequence variants in the TGFBR1 and TGFBR2 genes in nine of 70 unrelated individua

Recent Articles-Skeletal Muscle and Other Topics in Diabetes.

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The molecular genetics of Marfan syndrome and related disorders.

Marfan syndrome (MFS), a relatively common autosomal dominant hereditary disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the gene for fibrillin-1 (FBN1). The leading cause of premature death in untreated individuals with MFS is acute aortic dissection, which often follows a period of progressive dilatation of the ascending aorta. Recent research on the molecular physiology of fibrillin and the pathophysiology of MFS and related disorders has changed our understanding of this disorder by demonstrating cha

The role of bone-modifying agents in myeloma bone disease.

Bone disease is common in patients with multiple myeloma (MM), which manifests as bone pain and skeletal-related events (SREs) such as pathological fractures and spinal cord compression. Myeloma bone disease (MBD) can adversely affect the quality of life of patients and have negative effects on morbidity and mortality. The pathogenesis of MBD is complex, and several factors are involved in the dysregulation of bone metabolism and uncoupling of bone remodeling, which result in net bone loss and devastating SREs. Broadly speaking, elevated osteoclast activity, suppressed osteoblast activity, and

Myeloma Bone Disease: The Osteoblast in the Spotlight.

Lytic bone disease remains a life-altering complication of multiple myeloma, with up to 90% of sufferers experiencing skeletal events at some point in their cancer journey. This tumour-induced bone disease is driven by an upregulation of bone resorption (via increased osteoclast (OC) activity) and a downregulation of bone formation (via reduced osteoblast (OB) activity), leading to phenotypic osteolysis. Treatments are limited, and currently exclusively target OCs. Despite existing bone targeting therapies, patients successfully achieving remission from their cancer can still be left with chro

Myeloma Bone Disease: Update on Pathogenesis and Novel Treatment Strategies.

Bone disease, including osteolytic lesions and/or osteoporosis, is a common feature of multiple myeloma (MM). The consequences of skeletal involvement are severe pain, spinal cord compressions, and bone fractures, which have a dramatic impact on patients' quality of life and, ultimately, survival. During the past few years, several landmark studies significantly enhanced our insight into MM bone disease (MBD) by identifying molecular mechanisms leading to increased bone resorption due to osteoclast activation, and decreased bone formation by osteoblast inhibition. Bisphosphonates were the main

Взаимодействие между TH17 и центральной нервной системой в множестве склерозов.

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Myeloma Bone Disease: A Comprehensive Review.

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 patien

Carfilzomib Improves Bone Metabolism in Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results of the CarMMa Study.

Carfilzomib with dexamethasone (Kd) is a well-established regimen for the treatment of relapsed/refractory multiple myeloma (RRMM). There is limited information for the effects of Kd on myeloma-related bone disease. This non-interventional study aimed to assess skeletal-related events (SREs) and bone metabolism in patients with RRMM receiving Kd, in the absence of any bone-targeted agent. Twenty-five patients were enrolled with a median of three prior lines of therapy; 72% of them had evidence of osteolytic bone disease at study entry. During Kd treatment, the rate of new SREs was 28%. Kd prod

Metastatic bone disease: Pathogenesis and therapeutic options: Up-date on bone metastasis management.

Bone metastases (BM) are a common complication of cancer, whose management often requires a multidisciplinary approach. Despite the recent therapeutic advances, patients with BM may still experience skeletal-related events and symptomatic skeletal events, with detrimental impact on quality of life and survival. A deeper knowledge of the mechanisms underlying the onset of lytic and sclerotic BM has been acquired in the last decades, leading to the development of bone-targeting agents (BTA), mainly represented by anti-resorptive drugs and bone-seeking radiopharmaceuticals. Recent pre-clinical an

The complex regulation of TGF-β in cardiovascular disease.

Transforming growth factor β (TGF-β1) is a pleiotropic cytokine with many and complex effects in cell and tissue physiology. This is made possible by a very complex and interwoven signaling system, whose regulation continues to be the focus of a growing line of research. This complex regulation translates to a key role in cardiovascular physiology, hemostasis, and the blood-vessel interface. In accordance with this, the TGF-β1 pathway appears to be deregulated in related disorders, such as atherosclerotic vascular disease and myeloproliferative syndromes. It is expected that the growing amount

Прогресс в оказании поддержки в проведении обзора по множественным болезням, связанным с миеломой.

Множественная миелома (ММ) — неизлечимая порча плазменных клеток, характеризующаяся увеличением производства моноклонального иммуноглобулина. Пациенты с ММ подвержены высокому риску возникновения осложнений, связанных с заболеваниями. Остеолитическая болезнь костей one - из наиболее распространенных осложнений, связанных с заболеваниями, которые приводят к хронической боли и патологии скелета, что в значительной степени способствует высоким уровням заболеваемости и смертности среди пациентов с ОМ. Помимо стандартной антиММ-терапии, для улучшения качества жизни пациентов, страдающих ММ, необход

Bone Targeted Therapies for Bone Metastasis in Breast Cancer.

Cancer metastasis to the bone develops commonly in patients with various malignancies, and is a major cause of morbidity and diminished quality of life in many affected patients. Emerging treatments for metastatic bone disease have arisen from advances in our understanding of the unique cellular and molecular mechanisms that contribute to the bone metastasis. The tendency of cancer cells to metastasize to bone is probably the end result of many factors including vascular pathways, the highly vascular nature of the bone marrow (which increases the probability that cancer cells will be deposited

Blood outgrowth endothelial cells from Hereditary Haemorrhagic Telangiectasia patients reveal abnormalities compatible with vascular lesions.

OBJECTIVE: Hereditary haemorrhagic telangiectasia (HHT) is originated by mutations in endoglin (HHT1) and ALK1 (HHT2) genes. The purpose of this work was to isolate and characterize circulating endothelial cells from HHT patients. METHODS: Pure primary cultures of blood outgrowth endothelial cells (BOECs) were obtained from 50 ml of peripheral blood by selection on collagen plates with endothelial medium. RESULTS: The amount of endoglin in HHT1-BOECs is half the controls, but HHT2-BOECs are also endoglin-deficient. Since the TGF-beta/ALK1 pathway activates the endoglin promoter activity, the

Antibody-based therapies in multiple myeloma.

The unmet need for improved multiple myeloma (MM) therapy has stimulated clinical development of monoclonal antibodies (mAbs) targeting either MM cells or cells of the bone marrow (BM) microenvironment. In contrast to small-molecule inhibitors, therapeutic mAbs present the potential to specifically target tumor cells and directly induce an immune response to lyse tumor cells. Unique immune-effector mechanisms are only triggered by therapeutic mAbs but not by small molecule targeting agents. Although therapeutic murine mAbs or chimeric mAbs can cause immunogenicity, the advancement of genetic r

The Endosteal Niche in Breast Cancer Bone Metastasis.

The establishment of bone metastasis remains one of the most frequent complications of patients suffering from advanced breast cancer. Patients with bone metastases experience high morbidity and mortality caused by excessive, tumor-induced and osteoclast-mediated bone resorption. Anti-resorptive treatments, such as bisphosphonates, are available to ease skeletal related events including pain, increased fracture risk, and hypercalcemia. However, the disease remains incurable and 5-year survival rates for these patients are below 25%. Within the bone, disseminated breast cancer cells localize in

Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway.

Transforming growth factor-beta (TGF-β) signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically

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… Table 1 TGF-β receptors, their respective ligands, and canonical intracellular signaling proteins currently targeted by clinical investigation Notes: The TGF-β superfamily includes the following ligands: TGF-β1, TGF-β2, and TGF-β3; BMPs (BMP1–10); GDFs (GDF1–10); activins/inhibins (activin 1–5); nodal … Serine/threonine-protein kinase receptor R3 (SKR3) | TGF-β2 | TGF-β superfamily receptor type I (TSR-I) | TGF-β3 | Activin receptor-like kinase 1 (ALK1) | | TGF-β receptor type-1 (TGF-βRI) | TGF-β1 | SMAD2 | TGF-β2 | SMAD3 Alternative names: | TGF-β3 | Activin A receptor type II-like protein kinase …

The Metabolic Features of Osteoblasts: Implications for Multiple Myeloma (MM) Bone Disease.

The study of osteoblast (OB) metabolism has recently received increased attention due to the considerable amount of energy used during the bone remodeling process. In addition to glucose, the main nutrient for the osteoblast lineages, recent data highlight the importance of amino acid and fatty acid metabolism in providing the fuel necessary for the proper functioning of OBs. Among the amino acids, it has been reported that OBs are largely dependent on glutamine (Gln) for their differentiation and activity. In this review, we describe the main metabolic pathways governing OBs' fate and functio

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… Activin A is a transcriptional factor that regulates cell proliferation, differentiation, apoptosis, and metabolism [ 118 ]. High-circulating levels of activin A have been linked to MM progression and a poor prognosis [ 119 ]. … Activins as Dual Specificity TGF-beta Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors. Biomolecules. 2020;10:519. doi: 10.3390/biom10040519. 119. …