Osteoclasts in Multiple Myeloma Are Derived from Gr-1+CD11b+Myeloid-Derived Suppressor Cells

Abstract

Osteoclasts play a key role in the development of cancer-associated osteolytic lesions. The number and activity of osteoclasts are often enhanced by tumors. However, the origin of osteoclasts is unknown. Myeloid-derived suppressor cells (MDSCs) are one of the pre-metastatic niche components that are induced to expand by tumor cells. Here we show that the MDSCs can differentiate into mature and functional osteoclasts in vitro and in vivo. Inoculation of 5TGM1-GFP myeloma cells into C57BL6/KaLwRij mice led to a significant expansion of MDSCs in blood, spleen, and bone marrow over time. When grown in osteoclastogenic media in vitro, MDSCs from tumor-challenged mice displayed 14 times greater potential to differentiate into mature and functional osteoclasts than those from non-tumor controls. Importantly, MDSCs from tumor-challenged LacZ transgenic mice differentiated into LacZ+osteoclasts in vivo. Furthermore, a significant increase in tumor burden and bone loss accompanied by increased number of osteoclasts was observed in mice co-inoculated with tumor-challenged MDSCs and 5TGM1 cells compared to the control animals received 5TGM1 cells alone. Finally, treatment of MDSCs from myeloma-challenged mice with Zoledronic acid (ZA), a potent inhibitor of bone resorption, inhibited the number of osteoclasts formed in MDSC cultures and the expansion of MDSCs and bone lesions in mice. Collectively, these data provide in vitro and in vivo evidence that tumor-induced MDSCs exacerbate cancer-associated bone destruction by directly serving as osteoclast precursors.

Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication

“…45 In addition, MDSCs are OCPs and differentiate into OCs in the context of a RANKL-rich milieu. 46,47 Importantly, the differentiation of OCPs into OCs does not diminish their ability to inhibit T-cell proliferation. 45 We here observe that OCPs or immature OCs highly express immunecheckpoint molecules, thereby further conferring immune suppression in MM.…”

Tumor-Derived Osteopontin Suppresses Antitumor Immunity by Promoting Extramedullary Myelopoiesis

“…Recently, MDSCs have been suggested to be precursors of osteoclasts under tumor environment (49,50). Considering that osteopontin is a main component of the bone microenvironment (39), osteopontin might induce the proliferation of LK cells and subsequently expand the MDSCs that may serve as precursors of osteoclasts in the bone.…”

Pathogenesis beyond the cancer clone(s) in multiple myeloma

“…Several groups demonstrated the capacity of MMCs to expand MDSCs in murine models, which is hypothesized to contribute to myeloma pathogenesis at least in 2 ways: first, by exerting an antiproliferative effect against lymphocytes via increased nitric oxide production, L-arginine depletion, and IL-10 secretion; and second, by differentiating into OCs in the context of a RANKL-rich milieu. 103,104 Macrophages. Within the tumor microenvironment, MDSCs can also differentiate into tumor-associated macrophages (TAMs), which are phenotypically and functionally distinct from their precursor cells.…”