MicroRNAs as regulators of bone homeostasis and bone metastasis

Abstract

MicroRNAs (miRNAs) are short, endogenous RNAs that have essential roles in regulating gene expression through the disruption of target genes. The miRNA-induced suppression can occur through Argonaute-mediated cleavage of target mRNAs or by translational inhibition. System-wide studies have underscored the integral role that miRNAs play in regulating the expression of essential genes within bone marrow stromal cells. The miRNA expression has been shown to enhance or inhibit cell differentiation and activity, and elucidating miRNA targets within bone marrow cells has revealed novel regulations during normal bone development. Importantly, multiple studies have shown that miRNA misexpression mediates the progression of bone-related pathologies, including osteopetrosis and osteoporosis, as well as the development and progression of osteosarcoma. Furthermore, recent studies have detailed the capacity for miRNAs to influence bone metastasis from a number of primary carcinomas. Taken together, these findings reveal the significant clinical potential for miRNAs to regulate bone homeostasis, as well as to mediate bone-related pathologies.BoneKEy Reports 3, Article number: 549 (2014) | doi:10.1038/bonekey.2014.44 MiRNA Biogenesis and FunctionThe past decade has seen a torrent of novel research into the post-translational regulation of genes via microRNA-mediated suppression. The microRNAs (miRNAs) are a class of B22-nucleotide-long RNAs that repress gene expression through complementary binding to sites in the 3 0 -untranslated region (UTR) of target mRNAs. 1 Mature miRNAs are generated by the sequential cleavage of longer precursor transcripts, or pri-miRNAs, that are typically transcribed from intragenic or intergenic regions by RNA polymerase II. 2 The initial cleavage step, mediated by Drosha and the DGCR8 complex, occurs in the nucleus and produces a shortened (70-100 nucleotides) pre-miRNA hairpin. Pre-miRNAs are exported from the nucleus by Exportin 5, followed by a second cleavage by the ribonuclease Dicer that produces a double-stranded, B18-25-nucleotide-long mature miRNA. One miRNA strand will then combine with Argonaute (AGO2) proteins to produce an RNAinduced silencing complex, allowing for directed pairing with target mRNAs. 1

Tumour-derived miRNAs and bone metastasis

“…21 The profound alterations of bone homeostasis induced by in vivo deletion of Dicer and/or DGCR8/Ago2 in osteoprogenitor cells has suggested that tumour-secreted miRNAs might control bone cell differentiation and activity. 12 Aberrant expression of miRNAs assessed through miRNA profiling of human primary and skeletal tumours provide additional evidence that endogenous miRNAs regulate metastatic cells in primary sites and DTCs. Nonetheless, tumour-secreted factors induce specific miRNA signatures in tumour-associated stromal cells and in mature osteoclasts and its precursors during cancer-associated bone destruction.…”

“…12 Recent studies have also demonstrated how these miRNAs may be transferred from the bone marrow stromal cells to nearby cancer cells through gap junction intracellular communication. 58 Co-culture of MDA-MB-231 or T47D breast cancer cells with bone marrow stromal cells resulted in cell cycle arrest in the G0 phase.…”

“…Such observations have suggested that miRNAs could be used as diagnostic and prognostic biomarkers for patients with high risk of bone metastasis or relapse and for evaluation of treatment efficiency. 12,13 Evidence reporting that the profile of secreted miRNAs reflects their misexpression pattern both in tumour cells and bone stroma cells suggest the exciting possibility of using them as valuable index of the disease in regard of their stability and minimally invasive accessibility. 63 MiRNA expression in vitro and in vivo in mice preclinical models has been modulated by synthetic chemically miRNAs as both targets and tools ( Table 1).…”

“…10,11 Consequently, the dysregulation of miRNA expression in cancer cells not only impacts the intrinsic tumour cell properties and tumour-derived factors but also modulates the tumour-stromal crosstalk within primary tumour and metastatic site. 12 In this regard, miRNAs can control multiple aspects of bone metastasis including the initial steps of cancer cell escape from the primary tumour to the homing and invasion of bone, as well as secondary outgrowth and tumour-bone cell interactions 13 (Figure 1). A small subset of cancer cells in breast primary tumours express specific gene signatures that would be predictive of bone metastasis.…”

Bone marrow stroma-derived miRNAs as regulators, biomarkers and therapeutic targets of bone metastasis

“…[8][9][10] Inhibition of mRNA translation by miRNAs has emerged as an important regulator of developmental osteogenic signaling pathways, osteoblast growth and differentiation, osteoclast-mediated bone resorption activity and general bone homeostasis. Hence, it is not surprising that cell-type-specific disruption of miRNA biogenesis by deletion of Dicer would have a significant impact on physiological bone formation and remodeling ( Table 1).…”