Osteoblast suppression in multiple myeloma bone disease

Abstract

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.

Functional Comparison between Healthy and Multiple Myeloma Adipose Stromal Cells

“…MM is characterized by bone osteolytic lesions that result from an imbalance between osteoclastic and osteoblastic compartments [4,26]. Osteoblastic activity is downregulated in MM [16,27]. MM cells inhibit the differentiation of MSCs into osteoblasts by especially producing the Wnt inhibitor DKK1 [5,28].…”

“…Unfortunately, we and others have demonstrated that MSCs are abnormal in MM [12][13][14]; in particular, they produce not only excess MM growth factors such as interleukin-6 (IL-6) [15] but also growth and differentiation factor 15 (GDF15), which is also responsible for chemoprotection [8]. Importantly, their ability to differentiate in osteoblasts is severely impaired, even without any contact with MM cells [16], one explanation being their abnormally high secretion of the Wnt inhibitor Dickkopf 1 (DKK1).…”

The CaSR in Pathogenesis of Breast Cancer: A New Target for Early Stage Bone Metastases

“…Thus, it is quite understandable why most of the drugs in the market for bone metastatic patients are bone targeted. An interesting proposition about harnessing osteoblasts, based on data from patients, in vivo experiments, and co cultures, suggest that osteoblasts and their secretomes were hostile to growth of myeloma cells in the bone (124,125). Similar in vitro data in the case of breast cancer also showed that introduction of osteoblasts curbed bone turnover caused by osteolytic breast cancer (126).…”

The Emerging Role of Osteocytes in Cancer in Bone

“…Increased bone resorption releases bone matrix–embedded growth factors such as transforming growth factor beta (TGF‐β), which further stimulates tumor growth and bone destruction . Concomitantly, cancer cells secrete factors (interleukin [IL]‐7, IL‐3, Dickkopf Wnt Signaling Pathway Inhibitor 1 [DKK‐1], and Sclerostin) and promote epigenetic changes that suppress osteoblast differentiation and function (reviewed in Giuliani and colleagues, (28) MacDonald and Delgado‐Calle, and Adamik and colleagues). As a result, bone is resorbed at a rate faster than it is formed, causing the development of overt “osteolytic lesions,” which severely weakens the bone and elevates fracture risk.…”