MicroRNAs and Osteolytic Bone Metastasis: The Roles of MicroRNAs in Tumor-Induced Osteoclast Differentiation

Abstract

Osteolytic bone metastasis frequently occurs in the later stages of breast, lung, and several other cancers. Osteoclasts, the only cells that resorb bone, are hijacked by tumor cells, which break down bone remodeling systems. As a result, osteolysis occurs and may cause patients to suffer bone fractures, pain, and hypercalcemia. It is important to understand the mechanism of bone metastasis to establish new cancer therapies. MicroRNAs are small, noncoding RNAs that are involved in various biological processes, including cellular differentiation, proliferation, apoptosis, and tumorigenesis. MicroRNAs have significant clinical potential, including their use as new therapeutic targets and disease-specific biomarkers. Recent studies have revealed that microRNAs are involved in osteoclast differentiation and osteolytic bone metastasis. In this review focusing on microRNAs, the author discusses the roles of microRNAs in osteoclastogenesis and osteolytic bone metastasis.

Keywords: Bone Metastasis; Exosomes; Extracellular Vesicles; MicroRNAs; Osteoclasts.

Figure 1

An important signaling cascade of osteoclastogenesis. The binding of M-CSF to its receptor, c-Fms, induces the transcription factor c-Fos, whereas the binding of RANKL to its receptor, RANK, leads to the recruitment of TRAF6, the main adapter molecule of RANK. TRAF6 activates NF-κB and mitogen-activated kinases including JNK. JNK in turn activates the transcription factor c-Jun. RANKL/RANK also induces c-Fos to form AP-1, a heterodimeric transcription factor, with c-Jun. AP-1 and NF-κB then induce NFATc1, a master transcription factor that regulates osteoclast differentiation. NFATc1 works together with other transcription factors such as AP-1, PU.1, and MITF to induce various osteoclast-specific genes. Thus, M-CSF and RANKL signaling pathways are crucial for osteoclastogenesis. On the other hand, the RANK–RANKL interaction is inhibited by the decoy receptor OPG expressed by stromal cells and osteoblasts.

Figure 2

Schematic view of tumor-induced osteoclast formation. Bone-derived growth factors (IGFs, TGF-β and other growth factors) are released by osteoclastic bone resorption. These factors promote tumor cell proliferation and survival. TGF-β acts on tumor cells to produce growth factors, such as PTHrP and IL-11. PTHrP acts on osteoblasts and stromal cells and promotes the expression of RANKL, resulting in the enhancement of osteoclastogenesis and destruction of bone. Osteoclasts secrete extracellular vesicles (EVs) containing specific microRNAs, such as miR-21, miR-210, and miR-378. miR-16 and miR-378 are secreted biomarkers for osteolytic bone metastasis.