Bacterial infections exacerbate myeloma bone disease

Multiple myeloma is characterized by osteolytic lesions caused by reduced bone formation and activated bone resorption. An important feature of myeloma is a failure of bone healing after successful treatment. In this work, clinical studies indicated a highly positive correlation between bone marrow bacteria abundance and bone lesion numbers of myeloma patients in complete remission. Coculture experiments demonstrated that marrow Escherichia coli (E. coli) promotes osteoclast differentiation and inhibits osteoblast differentiation. Mechanism studies showed that E. coli lipopolysaccharides (LPS) activated NF-κB p65 signaling and reduced phosphorylated smad1/5/9 binding ability with RUNX2 promoter, leading to decreased RUNX2 expression in osteoblast progenitors. Additionally, LPS enhanced phosphorylated NF-κB p65 binding ability with NFATc1 promoter, leading to increased NFATc1 expression in osteoclast progenitors. In vivo studies revealed E. coli contributes to osteolytic bone lesion, and elimination of E. coli infection assists healing of bone lesion in mouse model of myeloma in complete remission. These findings establish a heretofore unrecognized effect for E. coli in the genesis of myeloma bone disease and suggest a new treatment strategy.

Circulating microRNAs Correlate with Multiple Myeloma and Skeletal Osteolytic Lesions

Multiple myeloma (MM) is the second most frequent hematological disease and can cause skeletal osteolytic lesions. This study aims to evaluate the expression of circulating microRNAs (miRNAs) in MM patients and to correlate those levels with clinicopathological features, including bone lesions. A panel of miRNAs associated with MM onset and progression, or with bone remodeling, was analyzed in the plasma of 82 subjects (47 MM patients; 35 healthy controls). Results show that miR-16-5p, miR-20a-5p, and miR-21-5p are differently expressed between MM patients and healthy controls. Receiver operating characteristic analyses indicate that their combined expression has potential as a molecular marker (Area Under the Curve, AUC of 0.8249). Furthermore, significant correlations were found between the analyzed miRNAs and disease stage, treatment, β2 microglobulin, serum albumin and creatinine levels, but not with calcium levels or genetic alterations. In this cohort, 65.96% of MM patients had bone lesions, the majority of which were in the vertebrae. Additionally, miR-29c-3p was decreased in patients with osteolytic lesions compared with patients without bone disease. Interestingly, circulating levels of miR-29b-3p correlated with cervical and thoracic vertebral lesions, while miR-195-5p correlated with thoracic lesions. Our findings suggest circulating miRNAs can be promising biomarkers for MM diagnosis and that their levels correlate with myeloma bone disease and osteolytic lesions.

Pathophysiological role of calcium channels and transporters in the multiple myeloma

Multiple myeloma (MM) is a common malignant tumor of plasma cells. Despite several treatment approaches in the past two decades, MM remains an aggressive and incurable disease in dire need of new treatment strategies. Approximately 70–80% of patients with MM have myeloma bone disease (MBD), often accompanied by pathological fractures and hypercalcemia, which seriously affect the prognosis of the patients. Calcium channels and transporters can mediate Ca2+ balance inside and outside of the membrane, indicating that they may be closely related to the prognosis of MM. Therefore, this review focuses on the roles of some critical calcium channels and transporters in MM prognosis, which located in the plasma membrane, endoplasmic reticulum and mitochondria. The goal of this review is to facilitate the identification of new targets for the treatment and prognosis of MM.

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 chronic pain, poor mobility, and reduced quality of life as a result of bone disease. As such, the field is desperately in need of new and improved bone-modulating therapeutic agents. One such option is the use of bone anabolics, drugs that are gaining traction in the osteoporosis field following successful clinical trials. The prospect of using these therapies in relation to myeloma is an attractive option, as they aim to stimulate OBs, as opposed to existing therapeutics that do little to orchestrate new bone formation. The preclinical application of bone anabolics in myeloma mouse models has demonstrated positive outcomes for bone repair and fracture resistance. Here, we review the role of the OB in the pathophysiology of myeloma-induced bone disease and explore whether novel OB targeted therapies could improve outcomes for patients.

An Improved Animal Model of Multiple Myeloma Bone Disease

Multiple myeloma (MM) is a plasma cell malignancy that causes an accumulation of terminally differentiated monoclonal plasma cells in the bone marrow, accompanied by multiple myeloma bone disease (MMBD). MM animal models have been developed and enable to interrogate the mechanism of MM tumorigenesis. However, these models demonstrate little or no evidence of MMBD. We try to establish the MMBD model with severe bone lesions and easily accessible MM progression. 1 × 106 luciferase-expressing 5TGM1 cells were injected into 8–12 week-old NOD SCID gamma mouse (NSG) and C57BL/KaLwRij mouse via the tail vein. Myeloma progression was assessed weekly via in vivo bioluminescence (BL) imaging using IVIS-200. The spine and femur/tibia were extracted and scanned by the micro-computer tomography for bone histo-morphometric analyses at the postmortem. The median survivals were 56 days in NSG while 44.5 days in C57BL/KaLwRij agreed with the BL imaging results. Histomorphic and DEXA analyses demonstrated that NSG mice have severe bone resorption that occurred at the lumbar spine but no significance at the femur compared to C57BL/KaLwRij mice. Based on these, we conclude that the systemic 5TGM1 injected NSG mouse slowly progresses myeloma and develops more severe MMBD than the C57BL/KaLwRij model.

Reelin depletion alleviates multiple myeloma bone disease by promoting osteogenesis and inhibiting osteolysis

Extracellular matrix glycoprotein Reelin is associated with tumor metastasis and prognosis in various malignancies. However, its effects on multiple myeloma (MM) are not fully understood. Here, we investigated the regulatory effects of Reelin on MM and its underlying pathogenic mechanisms. Lentivirus plasmid containing short hairpin RNA targeting Reelin (LV3-Reln) was transfected into SP2/0 cells to knockdown Reelin expression. Flow cytometry assay analyzed cell cycle and apoptosis while Transwell assay evaluated invasiveness. BALB/c mice were inoculated with LV3-Reln-transfected SP2/0 cells to establish MM model. Primary myeloma cells and osteoblasts/osteoclast were isolated from tumor tissue and limb long bones respectively. ELISA examined serum biomarkers and immunohistochemistry detected immunoglobulin light chain expression. Morphological changes and osteoclast/osteoblast differentiation were observed by histological staining. mRNA and proteins expression were determined by qPCR and WB. In vitro studies showed that Reelin depletion regulated osteolysis and osteogenesis balance, cell cycle, invasiveness, and apoptosis in SP2/0 cells. In LV3-Reln mice, tumor growth and invasiveness were suppressed, meanwhile, reduced osteoclast activation and enhanced osteoblast activity were observed. Reelin knockdown alleviated extramedullary morbidity and inhibited spleen immune cell apoptosis by down-regulating CDK5, IL-10, and Cyto-C expression. Furthermore, reduced Reelin expression restrained osteoclast differentiation while promoted osteogenesis in the bone of LV3-Reln mice. This was further supported by down-regulation of osteolytic specific mRNAs and proteins (Trap, Mmp9, Ctsk, Clcn7) and up-regulation of osteogenic specific ones (COL-1, Runx2, β-Catenin). Reelin exerted important impacts on myeloma development through rebalancing osteolysis and osteogenesis, thus might be a potential therapeutic target for MM.

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 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.