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Stem Cell Study May Lead to Bone Lesion Treatment for Multiple Myeloma Sufferers

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Review of “Upregulation of lncRNA MEG3 Promotes Osteogenic Differentiation of Mesenchymal Stem Cells from Multiple Myeloma Patients by Targeting BMP4 Transcription” from Stem Cells by Stuart P. Atkinson

Multiple myeloma (MM) is a malignant B‐cell disorder characterised by dysregulated bone remodeling [1, 2] ultimately leading to bone lesions. Several studies have highlighted that mesenchymal stem cells (MSCs) from MM patients display impaired osteogenic capacity, although the mechanisms mediating this impairment are not well understood. Now researchers from the laboratory of Bingzong Li (Second Affiliated Hospital of Soochow University, Suzhou, China) have begun to delineate said mechanisms through their studies into BMP4, which has critical roles in embryonic, hematopoietic and mesenchymal development [3-6]. Alongside BMP4, they also studied a long non‐coding RNA (lncRNA) maternally expressed gene 3 (MEG3) which is transcribed in the opposite orientation to BMP4, which they now report as a potential biomarker and therapeutic target in MM [7].

Initial assessment of the osteogenic differentiation of MM-MSCs found lower MEG3 and BMP4 expression compared to normal donor (ND)-MSCs. Subsequent BMP4 treatment of MM-MSCs in osteogenic differentiation medium for 2–3 weeks induced osteogenic differentiation, therefore linking the suppression of BMP4 in MM-MSCs to the suppression of osteogenic potential. To further investigate this link, the group used a lentiviral shRNA‐based system to reduce levels of BMP4 in ND-MSCs, and they found that this led to a decrease in osteogenic differentiation. Subsequent MEG3 lncRNA analysis found that MEG3 overexpression in MM-MSCs led to an increase in BMP4 transcription, which induced osteogenic differentiation, while MEG3 downregulation in ND-MSCs decreased BMP4 transcription and inhibited osteogenic differentiation.

The group then discovered that the regulatory regions of BMP4 contained a functional site that is activated by MEG3 so suggesting that the transcriptional regulation of BMP4 likely involved an RNA-mediated interaction. Interestingly, a SOX2 binding site lies within the MEG3 functional site, and while the researchers found no differences in SOX2 mRNA expression levels between ND‐MSCs vs MM‐MSCs during osteoblastic induction, siRNA‐mediated knockdown of SOX2 increased BMP4 transcription in MM‐MSCs. Chromatin IP assays found that SOX2 does bind to the BMP4 promoter at the MEG3 functional site, and the loss of MEG3 expression mediated increased binding of SOX2. This was further confirmed using RNA immunoprecipitation assays which discovered a SOX2-MEG3 interaction, all suggesting that MEG3 can block SOX2-mediated repression of BMP4 expression in MSCs, leading to an increase in osteogenic capacity.

This revealing study suggests that the lncRNA MEG3 represents both a biomarker and a target for therapeutic intervention in multiple myeloma. Such therapies will hopefully reduce bone-related problems that occur in MM patients, thereby increasing these patients’ quality of life.

References

  1. Raje N and Roodman GD Advances in the biology and treatment of bone disease in multiple myeloma. Clinical cancer research : an official journal of the American Association for Cancer Research 2011;17:1278-1286.
  2. Giuliani N, Rizzoli V, and Roodman GD Multiple myeloma bone disease: Pathophysiology of osteoblast inhibition. Blood 2006;108:3992-3996.
  3. Khurana S, Buckley S, Schouteden S, et al. A novel role of BMP4 in adult hematopoietic stem and progenitor cell homing via Smad independent regulation of integrin-alpha4 expression. Blood 2013;121:781-790.
  4. Koli K, Myllarniemi M, Vuorinen K, et al. Bone morphogenetic protein-4 inhibitor gremlin is overexpressed in idiopathic pulmonary fibrosis. The American journal of pathology 2006;169:61-71.
  5. Rosendahl A, Pardali E, Speletas M, et al. Activation of bone morphogenetic protein/Smad signaling in bronchial epithelial cells during airway inflammation. Am J Respir Cell Mol Biol 2002;27:160-169.
  6. Marshall CJ, Kinnon C, and Thrasher AJ Polarized expression of bone morphogenetic protein-4 in the human aorta-gonad-mesonephros region. Blood 2000;96:1591-1593.
  7. Zhuang W, Ge X, Yang S, et al. Upregulation of lncRNA MEG3 Promotes Osteogenic Differentiation of Mesenchymal Stem Cells From Multiple Myeloma Patients By Targeting BMP4 Transcription. Stem Cells 2015;33:1985-1997.