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Bacterial infections exacerbate myeloma bone disease.

ABSTRACT: 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.

SUBMITTER: Liu R

PROVIDER: S-EPMC8734283 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Tumor-derived extracellular vesicles inhibit osteogenesis and exacerbate myeloma bone disease.

Project description:Background: As a hallmark driver of multiple myeloma (MM), MM bone disease (MBD) is unique in that it is characterized by severely impaired osteoblast activity resulting from blocked osteogenesis in bone marrow-derived mesenchymal stem cells (BM-MSCs). The mechanisms underlying this preferential blockade are incompletely understood. Methods: miRNA expression of MM cell-derived extracellular vesicles (MM-EVs) was detected by RNA sequencing. MM-EVs impaired osteogenesis and exacerbated MBD were in vitro and in vivo validated by histochemical staining, qPCR and micro-CT. We additionally examined the correlation between CD138+ circulating EVs (cirEVs) count and bone lesion in de novo MM patients. Results: Here, by sequencing and bioinformatics analysis, we found that MM-EVs were enriched in various molecules negatively regulating osteogenesis. We experimentally verified that MM-EVs inhibited BM-MSC osteogenesis, induced elevated expression of miR-103a-3p inhibiting osteogenesis in BM-MSCs, and increased cell viability and interleukin-6 secretion in MM cells. In a mouse model, MM-EVs that were injected into the marrow space of the left tibia led to impaired osteogenesis and exacerbated MBD and MM progression. Furthermore, the levels of CD138+ cirEVs in the peripheral blood were positively correlated with the number of MM bone lesions in MM patients. Conclusions: These findings suggest that MM-EVs play a pivotal role in the development of severely impaired osteoblast activity, which represents a novel biomarker for the precise diagnosis of MBD and a compelling rationale for exploring MM-EVs as a therapeutic target.

| S-EPMC6332790 | biostudies-literature

Mechanisms of multiple myeloma bone disease.

Project description:Multiple myeloma is the second most common hematological malignancy and the most frequent cancer to involve the skeleton. Multiple myeloma bone disease (MMBD) is characterized by abnormal bone remodeling with dysfunction of both bone resorption and bone formation, and thus can be used as a paradigm for other inflammatory bone diseases, and the regulation of osteoclasts and osteoblasts in malignancy. Studies of MMBD have identified novel regulators that increase osteoclastogenesis and osteoclast function, repress osteoblast differentiation, increase angiogenesis, or permanently alter stromal cells. This review will discuss the current understanding of mechanisms of osteoclast and osteoblast regulation in MMBD, and therapeutic approaches currently in use and under development that target mediators of bone destruction and blockade of bone formation for myeloma patients, including new anabolic therapies.

| S-EPMC3727863 | biostudies-other

Osteoblast suppression in multiple myeloma bone disease.

Project description:Multiple myeloma (MM) is the most frequent cancer to involve the skeleton with patients developing osteolytic bone lesions due to hyperactivation of osteoclasts and suppression of BMSCs differentiation into functional osteoblasts. Although new therapies for MM have greatly improved survival, MM remains incurable for most patients. Despite the major advances in current anti-MM and anti-resorptive treatments that can significantly improve osteolytic bone lysis, many bone lesions can persist even after therapeutic remission of active disease. Bone marrow mesenchymal stem cells (BMSCs) from MM patients are phenotypically distinct from their healthy counterparts and the mechanisms associated with the long-term osteogenic suppression are largely unknown. In this review we will highlight recent results of transcriptomic profiling studies that provide new insights into the establishment and maintenance of the persistent pathological alterations in MM-BMSCs that occur in MM. We will we discuss the role of genomic instabilities and senescence in propagating the chronically suppressed state and pro-inflammatory phenotype associated with MM-BMSCs. Lastly we describe the role of epigenetic-based mechanisms in regulating osteogenic gene expression to establish and maintain the pro-longed suppression of MM-BMSC differentiation into functional OBs.

| S-EPMC6303385 | biostudies-other

Multiple myeloma mesenchymal stromal cells: Contribution to myeloma bone disease and therapeutics.

Project description:Multiple myeloma is a hematological malignancy in which clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic lesions due to increased osteoclast (OC) activity and suppressed osteoblast (OB) function is characteristic of the disease. The bone marrow mesenchymal stromal cells (MSCs) play a critical role in multiple myeloma pathophysiology, greatly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of myeloma bone disease (MBD), together with the reported genomic, functional and gene expression differences between MSCs derived from myeloma patients (pMSCs) and their healthy counterparts (dMSCs). Being MSCs the progenitors of OBs, pMSCs primarily contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequence of multiple OB inhibitory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs also readily contribute to MBD by promoting OC formation and activity at various levels (i.e., increasing RANKL to OPG expression, augmenting secretion of activin A, uncoupling ephrinB2-EphB4 signaling, and through augmented production of Wnt5a), thus further contributing to OB/OC uncoupling in osteolytic lesions. In this review, we also look over main signaling pathways involved in the osteogenic differentiation of MSCs and/or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents (at preclinical or clinical stage) targeting those signaling pathways is commented.

| S-EPMC4131274 | biostudies-literature

MicroRNAs in multiple myeloma and related bone disease.

Project description:MicroRNAs (miRNAs) are short non coding RNAs aberrantly expressed in solid and hematopoietic malignancies where they play a pivotal function as post-transcriptional regulators of gene expression. Recent reports have unveiled a central role of miRNAs in multiple myeloma onset and progression and preclinical findings are progressively disclosing their potential therapeutic value as drugs or targets. In this review, we provide the basic insights of miRNA biology and function, showing how these molecules are extensively dysregulated in malignant plasma cells (PC) and related microenvironment, thus favoring clone survival and proliferation. We here describe how these critical activities have recently been evaluated to design miRNA-based therapies against multiple myeloma cells and its surrounding microenvironment.

| S-EPMC4690997 | biostudies-literature

Pathogenesis and treatment of multiple myeloma bone disease.

Project description:Multiple myeloma (Plasma cell myeloma), a malignancy of the plasma cells, exhibits tumor expansion preferentially in the bone marrow and the development of bone-destructive lesions. Multiple myeloma is still an incurable disease with changes in the bone marrow microenvironment in favor of the survival and proliferation of multiple myeloma cells and bone destruction. In this review, we described the recent findings on the regulators involved in the development of myeloma bone diseases, and succinctly summarize currently available therapeutic options and the development of novel bone modifying agents for myeloma treatment.

| S-EPMC8477206 | biostudies-literature

Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease.

Project description:Despite evidence about the implication of the bone marrow (BM) stromal microenvironment in multiple myeloma (MM) cell growth and survival, little is known about the effects of myelomatous cells on BM stromal cells. Mesenchymal stromal cells (MSCs) from healthy donors (dMSCs) or myeloma patients (pMSCs) were co-cultured with the myeloma cell line MM.1S, and the transcriptomic profile of MSCs induced by this interaction was analyzed. Deregulated genes after co-culture common to both d/pMSCs revealed functional involvement in tumor microenvironment cross-talk, myeloma growth induction and drug resistance, angiogenesis and signals for osteoclast activation and osteoblast inhibition. Additional genes induced by co-culture were exclusively deregulated in pMSCs and predominantly associated to RNA processing, the ubiquitine-proteasome pathway, cell cycle regulation, cellular stress and non-canonical Wnt signaling. The upregulated expression of five genes after co-culture (CXCL1, CXCL5 and CXCL6 in d/pMSCs, and Neuregulin 3 and Norrie disease protein exclusively in pMSCs) was confirmed, and functional in vitro assays revealed putative roles in MM pathophysiology. The transcriptomic profile of pMSCs co-cultured with myeloma cells may better reflect that of MSCs in the BM of myeloma patients, and provides new molecular insights to the contribution of these cells to MM pathophysiology and to myeloma bone disease.

| S-EPMC4226683 | biostudies-literature

Non-Coding RNAs in Multiple Myeloma Bone Disease Pathophysiology.

Project description:Bone remodeling is uncoupled in the multiple myeloma (MM) bone marrow niche, resulting in enhanced osteoclastogenesis responsible of MM-related bone disease (MMBD). Several studies have disclosed the mechanisms underlying increased osteoclast formation and activity triggered by the various cellular components of the MM bone marrow microenvironment, leading to the identification of novel targets for therapeutic intervention. In this regard, recent attention has been given to non-coding RNA (ncRNA) molecules, that finely tune gene expression programs involved in bone homeostasis both in physiological and pathological settings. In this review, we will analyze major signaling pathways involved in MMBD pathophysiology, and report emerging evidence of their regulation by different classes of ncRNAs.

| S-EPMC7549375 | biostudies-literature

New agents in the Treatment of Myeloma Bone Disease.

Project description:Patients with multiple myeloma develop a devastating bone disease driven by the uncoupling of bone remodelling, excess osteoclastic bone resorption and diminished osteoblastic bone formation. The bone phenotype is typified by focal osteolytic lesions leading to pathological fractures, hypercalcaemia and other catastrophic bone events such as spinal cord compression. This causes bone pain, impaired functional status, decreased quality of life and increased mortality. Early in the disease, malignant plasma cells occupy a niche environment that encompasses their interaction with other key cellular components of the bone marrow microenvironment. Through these interactions, osteoclast-activating factors and osteoblast inhibitory factors are produced, which together uncouple the dynamic process of bone remodelling, leading to net bone loss and focal osteolytic lesions. Current management includes antiresorptive therapies, i.e. bisphosphonates, palliative support and orthopaedic interventions. Bisphosphonates are the mainstay of treatment for myeloma bone disease (MBD), but are only partially effective and do have some significant disadvantages; for example, they do not lead to the repair of existing bone destruction. Thus, newer agents to prevent bone destruction and also promote bone formation and repair existing lesions are warranted. This review summarises novel ways that MBD is being therapeutically targeted.

| S-EPMC5805798 | biostudies-literature

Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease.

Project description:Osteolytic lesions in multiple myeloma are caused by osteoclast-mediated bone resorption and reduced bone formation. A unique feature of myeloma is a failure of bone healing after successful treatment. We observed adipocytes on trabecular bone near the resorbed area in successfully treated patients. Normal marrow adipocytes, when cocultured with myeloma cells, were reprogrammed and produced adipokines that activate osteoclastogenesis and suppress osteoblastogenesis. These adipocytes have reduced expression of peroxisome proliferator-activated receptor γ (PPARγ) mediated by recruitment of polycomb repressive complex 2 (PRC2), which modifies PPARγ promoter methylation at trimethyl lysine-27 histone H3. We confirmed the importance of methylation in the PPARγ promoter by demonstrating that adipocyte-specific knockout of EZH2, a member of the PRC2, prevents adipocyte reprogramming and reverses bone changes in a mouse model. We validated the strong correlation between the frequency of bone lesions and the expression of EZH2 in marrow adipocytes from patients in remission. These results define a role for adipocytes in genesis of myeloma-associated bone disease and that reversal of adipocyte reprogramming has therapeutic implications.

| S-EPMC6999853 | biostudies-literature

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