Review
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World J Stem Cells. Jul 26, 2014; 6(3): 322-343
Published online Jul 26, 2014. doi: 10.4252/wjsc.v6.i3.322
Multiple myeloma mesenchymal stromal cells: Contribution to myeloma bone disease and therapeutics
Antonio Garcia-Gomez, Fermin Sanchez-Guijo, M Consuelo del Cañizo, Jesus F San Miguel, Mercedes Garayoa
Antonio Garcia-Gomez, Fermin Sanchez-Guijo, Jesus F San Miguel, Mercedes Garayoa, Cancer Research Center, IBMCC (University of Salamanca-CSIC), 37007 Salamanca, Spain
Antonio Garcia-Gomez, Fermin Sanchez-Guijo, M Consuelo del Cañizo, Mercedes Garayoa, Jesús F San Miguel, Institute of Biomedical Research of Salamanca, University Hospital, 37007 Salamanca, Spain
Antonio Garcia-Gomez, Fermin Sanchez-Guijo, M Consuelo del Cañizo, Jesus F San Miguel, Mercedes Garayoa, Network of Centers for Regenerative Medicine and Cellular Therapy from Castilla y León, 37007 Salamanca, Spain
Fermin Sanchez-Guijo, M Consuelo del Cañizo, Spanish Cooperative Research Network in Cellular Therapy, 28029 Madrid, Spain
Jesus F San Miguel, Center for Applied Biomedical Research, Clinic University of Navarra, 31008 Pamplona, Spain
Author contributions: Garcia-Gomez A, Sanchez-Guijo F, del Cañizo MC and Garayoa M drafted and designed the manuscript; Garcia-Gomez A, Sanchez-Guijo F and Garayoa M summarized and wrote the manuscript; Garcia-Gomez A prepared the figures; Garcia-Gomez A and Sanchez-Guijo F prepared the tables; Garcia-Gomez A, Sanchez-Guijo F, del Cañizo MC, San Miguel JF and Garayoa M critically revised, edited and approved the manuscript.
Supported by Grants from the Spanish Ministry of Economía y Competitividad-Instituto de Salud Carlos III, No. PI12/02591; European Funds for Regional Development; the Spanish Health Thematic Networks of Cooperative Research in Cancer, No. RTICC RD12/0036/0058; Cellular Therapy, No. TerCel RD12/0019/0001, group 8; the Network of Centers for Regenerative Medicine and Cellular Therapy from Castilla y León; and the Spanish Society of Hematology and Hemotherapy (to Garcia-Gomez A)
Correspondence to: Mercedes Garayoa, PhD, Cancer Research Center, IBMCC (University of Salamanca-CSIC), Campus Miguel de Unamuno, Avda. Coimbra s/n, 37007 Salamanca, Spain. mgarayoa@usal.es
Telephone: +34-923-294812 Fax: +34-923-294743
Received: November 15, 2013
Revised: May 12, 2014
Accepted: June 10, 2014
Published online: July 26, 2014
Processing time: 246 Days and 16.1 Hours
Abstract

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.

Keywords: Mesenchymal stromal cells; Multiple myeloma; Osteolytic lesions; Myeloma bone disease; Bone-directed therapy; Bone-anabolic drugs

Core tip: In multiple myeloma, bone marrow mesenchymal stromal cells (MSCs) primarily contribute to associated osteolytic lesions because of their defective differentiation to mature osteoblasts. Importantly, these MSCs also contribute to myeloma bone disease by enhancing osteoclast formation and activity through various mechanisms (i.e., increasing the receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio, augmenting activin A secretion, uncoupling ephrinB2-EphB4 signaling and because of heightened production of Wnt5a). In addition, we overview signaling pathways involved in the osteogenic differentiation of MSCs or osteoblast activity and comment on the reported activity of bone-anabolic agents (preclinical or clinical stage) to restore bone homeostasis in myeloma patients.