Dynamic interplay between bone and multiple myeloma: Emerging roles of the osteoblast

Abstract

Multiple myeloma is a B-cell malignancy characterized by the unrelenting proliferation of plasma cells. Multiple myeloma causes osteolytic lesions and fractures that do not heal due to decreased osteoblastic and increased osteoclastic activity. However, the exact relationship between osteoblasts and myeloma cells remains elusive. Understanding the interactions between these dynamic bone-forming cells and myeloma cells is crucial to understanding how osteolytic lesions form and persist, and how tumors grow within the bone marrow. This review provides a comprehensive overview of basic and translational research focused on the role of osteoblasts in multiple myeloma progression and their relationship to osteolytic lesions. Importantly, current challenges for in vitro studies exploring direct osteoblastic effects on myeloma cells, and gaps in understanding the role of the osteoblast in myeloma progression are delineated. Finally, successes and challenges in myeloma treatment with osteoanabolic therapy (i.e. any treatment that induces increased osteoblastic number or activity) are enumerated. Our goal is to illuminate novel mechanisms by which osteoblasts may contribute to multiple myeloma disease progression and osteolysis to better direct research efforts. Ultimately, we hope this may provide a roadmap for new approaches to the pathogenesis and treatment of multiple myeloma with a particular focus on the osteoblast.

Cell Adhesion Molecule CD166 Drives Malignant Progression and Osteolytic Disease in Multiple Myeloma

“…However, this balance is broken during bone destruction caused by the presence of cancer cells (37,38). Therefore, MM-associated change in bone remodeling may result from CD166-mediated suppression of osteoblastogenesis or enhancement of osteoclastogenesis.…”

Navigating the bone marrow niche: translational insights and cancer-driven dysfunction

“…For example, MSCs from patients with multiple myeloma and myelodysplastic syndrome are abnormal due to the effects of local tumour cells, and have inhibited osteogenesis and increased tumour-supportive functions, which are driven through numerous mechanisms. 80–82 Similarly, leukaemic myeloid cells also ‘hijack’ the normal osteogenic process by stimulating MSCs to overproduce functionally altered osteoblast-lineage cells, which accumulate in the bone marrow cavity as inflammatory myelofibrotic cells. 83 These myeloproliferative neoplasia-associated osteoblasts, in turn, exhibit decreased expression of many HSC-retention factors and have a severely compromised ability to maintain normal HSCs, but are more efficient at harbouring laeukemia stem cells.…”

“…82 Osteoblasts might also have an anti-leukaemic role, 98 and osteoblast numbers are significantly deceased in leukaemia. 72 Our review published in early 2015 discussed the roles of endosteal osteoblasts and bone marrow adipocytes in myeloma 82 and others have reviewed this topic for breast and prostate cancers.…”

“…82 Osteoblasts might also have an anti-leukaemic role, 98 and osteoblast numbers are significantly deceased in leukaemia. 72 Our review published in early 2015 discussed the roles of endosteal osteoblasts and bone marrow adipocytes in myeloma 82 and others have reviewed this topic for breast and prostate cancers. 99 The newly appreciated roles of osteocyte signalling, specifically the osteocyte-derived Wnt-inhibitor sclerostin, from lacunae to healthy and cancerous bone marrow niches, has also been reviewed in a 2014 publication.…”

The Impact of Mast Cell Density on the Progression of Bone Disease in Multiple Myeloma Patients

“…The study of this interplay has progressed significantly, and the disease pathology is becoming a more feasible therapeutic target. Nevertheless, this aspect of MM growth remains a major problem for MM patients [1,2]. …”