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Multiple Myeloma Bone Disease—Symptoms, Diagnosis and Treatment

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 January 2021) | Viewed by 26670

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Special Issue Editor

Prof. Dr. Franziska Jundt

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Guest Editor

Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
Interests: myeloma bone disease; bone marrow microenvironment; signaling pathways; mechanical stimuli of bone; MOPC315.BM murine model
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Multiple myeloma (MM) remains a rarely curable plasma cell disorder in the bone marrow, in which 80% of patients already at diagnosis show signs of bone disease, including osteolytic bone destruction and osteoporosis, with symptoms of severe pain and fractures. Due to skeletal-related pathologies, morbidity and mortality of patients is increased, affecting their quality of life. MM cells interfere with bone homeostasis by inhibiting osteoblast function and stimulating osteoclast activity, resulting in massive bone destruction and often multiple focal lesions. The use of bisphosphonates, local irradiation, and orthopedic intervention are standard treatment options. Current therapies often fail to heal bone lesions and to regenerate bone tissue even if active disease is absent. New approaches are needed for better detection and improved monitoring of bone structural changes, particularly in very early stages of the disease, before lytic lesions develop. In this Special Issue, we welcome contributions to all aspects of pathobiology, symptoms, diagnostic tools, and novel treatment options of MM bone disease. Preclinical fundamental and translational work is encouraged, including studies in precursor cells of the bone microenvironment, mouse studies, and novel bioreactor systems to imitate the cell–cell interactions between MM cells and their microenvironment.

Prof. Dr. Franziska Jundt
Guest Editor

Manuscript Submission Information

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Keywords

Mouse studies
Bone microenvironment
Mesenchymal stem cells
Signaling pathways
Cell–cell interactions
Imaging techniques
Novel biomarkers

Published Papers (7 papers)

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Research

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14 pages, 2137 KiB

Open AccessArticle

Prevention of Bone Destruction by Mechanical Loading Is Not Enhanced by the Bruton’s Tyrosine Kinase Inhibitor CC-292 in Myeloma Bone Disease

by Fani Ziouti, Maximilian Rummler, Beatrice Steyn, Tobias Thiele, Anne Seliger, Georg N. Duda, Bjarne Bogen, Bettina M. Willie and Franziska Jundt

Int. J. Mol. Sci. 2021, 22(8), 3840; https://doi.org/10.3390/ijms22083840 - 07 Apr 2021

Cited by 2 | Viewed by 2387

Abstract

Limiting bone resorption and regenerating bone tissue are treatment goals in myeloma bone disease (MMBD). Physical stimuli such as mechanical loading prevent bone destruction and enhance bone mass in the MOPC315.BM.Luc model of MMBD. It is unknown whether treatment with the Bruton’s tyrosine kinase inhibitor CC-292 (spebrutinib), which regulates osteoclast differentiation and function, augments the anabolic effect of mechanical loading. CC-292 was administered alone and in combination with axial compressive tibial loading in the MOPC315.BM.Luc model for three weeks. However, neither CC-292 alone nor its use in combination with mechanical loading was more effective in reducing osteolytic bone disease or rescuing bone mass than mechanical stimuli alone, as evidenced by microcomputed tomography (microCT) and histomorphometric analysis. Further studies are needed to investigate novel anti-myeloma and anti-resorptive strategies in combination with physical stimuli to improve treatment of MMBD. Full article

(This article belongs to the Special Issue Multiple Myeloma Bone Disease—Symptoms, Diagnosis and Treatment)

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14 pages, 2901 KiB

Open AccessArticle

The HGF/Met/NF-κB Pathway Regulates RANKL Expression in Osteoblasts and Bone Marrow Stromal Cells

by Masanobu Tsubaki, Shiori Seki, Tomoya Takeda, Akiko Chihara, Yuuko Arai, Yuusuke Morii, Motohiro Imano, Takao Satou, Kazunori Shimomura and Shozo Nishida

Int. J. Mol. Sci. 2020, 21(21), 7905; https://doi.org/10.3390/ijms21217905 - 24 Oct 2020

Cited by 10 | Viewed by 2157

Abstract

Multiple myeloma (MM)-induced bone disease occurs through hyperactivation of osteoclasts by several factors secreted by MM cells. MM cell-secreted factors induce osteoclast differentiation and activation via direct and indirect actions including enhanced expression of receptor activator of nuclear factor κB ligand (RANKL) in osteoblasts and bone marrow stromal cells (BMSCs). Hepatocyte growth factor (HGF) is elevated in MM patients and is associated with MM-induced bone disease, although the mechanism by which HGF promotes bone disease remains unclear. In the present study, we demonstrated that HGF induces RANKL expression in osteoblasts and BMSCs, and investigated the mechanism of induction. We found that HGF and MM cell supernatants induced RANKL expression in ST2 cells, MC3T3-E1 cells, and mouse BMSCs. In addition, HGF increased phosphorylation of Met and nuclear factor κB (NF-κB) in ST2 cells, MC3T3-E1 cells, or mouse BMSCs. Moreover, Met and NF-κB inhibitors suppressed HGF-induced RANKL expression in ST2 cells, MC3T3-E1 cells, and mouse BMSCs. These results indicated that HGF promotes RANKL expression in osteoblasts and BMSCs via the Met/NF-κB signaling pathway, and Met and NF-κB inhibitors suppressed HGF-induced RANKL expression. Our findings suggest that Met and NF-κB inhibitors are potentially useful in mitigating MM-induced bone disease in patients expressing high levels of HGF. Full article

(This article belongs to the Special Issue Multiple Myeloma Bone Disease—Symptoms, Diagnosis and Treatment)

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Review

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21 pages, 2999 KiB

Open AccessReview

Myeloma Bone Disease: A Comprehensive Review

by Shiva Kumar Reddy Mukkamalla and Dhatri Malipeddi

Int. J. Mol. Sci. 2021, 22(12), 6208; https://doi.org/10.3390/ijms22126208 - 08 Jun 2021

Cited by 26 | Viewed by 3834

Abstract

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. Full article

(This article belongs to the Special Issue Multiple Myeloma Bone Disease—Symptoms, Diagnosis and Treatment)

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18 pages, 1618 KiB

Open AccessReview

Molecular Mechanisms of Canine Osteosarcoma Metastasis

by Sylwia S. Wilk and Katarzyna A. Zabielska-Koczywąs

Int. J. Mol. Sci. 2021, 22(7), 3639; https://doi.org/10.3390/ijms22073639 - 31 Mar 2021

Cited by 12 | Viewed by 7580

Abstract

Osteosarcoma (OSA) represents the most common bone tumor in dogs. The malignancy is highly aggressive, and most of the dogs die due to metastasis, especially to the lungs. The metastatic process is complex and consists of several main steps. Assessment of the molecular mechanisms of metastasis requires in vitro and especially in vivo studies for a full evaluation of the process. The molecular and biological resemblance of canine OSA to its human counterpart enables the utilization of dogs as a spontaneous model of this disease in humans. The aim of the present review article is to summarize the knowledge of genes and proteins, including p63, signal transducer and activator of transcription 3 (STAT3), Snail2, ezrin, phosphorylated ezrin-radixin-moesin (p-ERM), hepatocyte growth factor-scatter factor (HGF-SF), epidermal growth factor receptor (EGFR), miR-9, and miR-34a, that are proven, by in vitro and/or in vivo studies, to be potentially involved in the metastatic cascade of canine OSA. The determination of molecular targets of metastatic disease may enhance the development of new therapeutic strategies. Full article

(This article belongs to the Special Issue Multiple Myeloma Bone Disease—Symptoms, Diagnosis and Treatment)

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14 pages, 703 KiB

Open AccessReview

Management of Myeloma Bone Lesions

by Jeng-Shiun Du, Chia-Hung Yen, Chin-Mu Hsu and Hui-Hua Hsiao

Int. J. Mol. Sci. 2021, 22(7), 3389; https://doi.org/10.3390/ijms22073389 - 25 Mar 2021

Cited by 7 | Viewed by 3808

Abstract

Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal plasma–cell proliferation. The survival and prognosis of this condition have been significantly improved by treatment with active anti-MM drugs such as bortezomib or lenalidomide. Further, the discovery of novel agents has recently paved the way for new areas of investigation. However, MM, including myeloma-related bone diseases, remains fatal. Bone disease or bone destruction in MM is a consequence of skeletal involvement with bone pain, spinal cord compression, and bone fracture resulting from osteolytic lesions. These consequences affect disease outcomes, including patients’ quality of life and survival. Several studies have sought to better understand MM bone disease (MBD) through the classification of its molecular mechanisms, including osteoclast activation and osteoblast inhibition. Bisphosphonates and the receptor activator of the nuclear factor-kappa B (NF-κB) ligand (RANKL) inhibitor, denosumab, prevent skeletal-related events in MM. In addition, several other bone-targeting agents, including bone-anabolic drugs, are currently used in preclinical and early clinical evaluations. This review summarizes the current knowledge of the pathogenesis of MBD and discusses novel agents that appear very promising and will soon enter clinical development. Full article

(This article belongs to the Special Issue Multiple Myeloma Bone Disease—Symptoms, Diagnosis and Treatment)

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18 pages, 1106 KiB

Open AccessReview

Multiple Myeloma Bone Disease: Implication of MicroRNAs in Its Molecular Background

by Aristea-Maria Papanota, Paraskevi Karousi, Christos K. Kontos, Ioannis Ntanasis-Stathopoulos, Andreas Scorilas and Evangelos Terpos

Int. J. Mol. Sci. 2021, 22(5), 2375; https://doi.org/10.3390/ijms22052375 - 27 Feb 2021

Cited by 18 | Viewed by 2717

Abstract

Multiple myeloma (MM) is a common hematological malignancy arising from terminally differentiated plasma cells. In the majority of cases, symptomatic disease is characterized by the presence of bone disease. Multiple myeloma bone disease (MMBD) is a result of an imbalance in the bone-remodeling process that leads to increased osteoclast activity and decreased osteoblast activity. The molecular background of MMBD appears intriguingly complex, as several signaling pathways and cell-to-cell interactions are implicated in the pathophysiology of MMBD. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of their target mRNAs. Numerous miRNAs have been witnessed to be involved in cancer and hematological malignancies and their role has been characterized either as oncogenic or oncosuppressive. Recently, scientific research turned towards miRNAs as regulators of MMBD. Scientific data support that miRNAs finely regulate the majority of the signaling pathways implicated in MMBD. In this review, we provide concise information regarding the molecular pathways with a significant role in MMBD and the miRNAs implicated in their regulation. Moreover, we discuss their utility as molecular biomarkers and highlight the putative usage of miRNAs as novel molecular targets for targeted therapy in MMBD. Full article

(This article belongs to the Special Issue Multiple Myeloma Bone Disease—Symptoms, Diagnosis and Treatment)

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22 pages, 803 KiB

Open AccessReview

Role of microRNAs in Diagnosis, Prognosis and Management of Multiple Myeloma

by Amro M. Soliman, Teoh Seong Lin, Pasuk Mahakkanukrauh and Srijit Das

Int. J. Mol. Sci. 2020, 21(20), 7539; https://doi.org/10.3390/ijms21207539 - 13 Oct 2020

Cited by 13 | Viewed by 3144

Abstract

Multiple myeloma (MM) is a cancerous bone disease characterized by malignant transformation of plasma cells in the bone marrow. MM is considered to be the second most common blood malignancy, with 20,000 new cases reported every year in the USA. Extensive research is currently enduring to validate diagnostic and therapeutic means to manage MM. microRNAs (miRNAs) were shown to be dysregulated in MM cases and to have a potential role in either progression or suppression of MM. Therefore, researchers investigated miRNAs levels in MM plasma cells and created tools to test their impact on tumor growth. In the present review, we discuss the most recently discovered miRNAs and their regulation in MM. Furthermore, we emphasized utilizing miRNAs as potential targets in the diagnosis, prognosis and treatment of MM, which can be useful for future clinical management. Full article

(This article belongs to the Special Issue Multiple Myeloma Bone Disease—Symptoms, Diagnosis and Treatment)

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