miRNA-34c regulates Notch signaling during bone development

Abstract

During bone homeostasis, osteoblast and osteoclast differentiation is coupled and regulated by multiple signaling pathways and their downstream transcription factors. Here, we show that microRNA 34 (miR-34) is significantly induced by BMP2 during osteoblast differentiation. In vivo, osteoblast-specific gain of miR-34c in mice leads to an age-dependent osteoporosis due to the defective mineralization and proliferation of osteoblasts and increased osteoclastogenesis. In osteoblasts, miR-34c targets multiple components of the Notch signaling pathway, including Notch1, Notch2 and Jag1 in a direct manner, and influences osteoclast differentiation in a non-cell-autonomous fashion. Taken together, our results demonstrate that miR-34c is critical during osteoblastogenesis in part by regulating Notch signaling in bone homeostasis. Furthermore, miR-34c-mediated post-transcriptional regulation of Notch signaling in osteoblasts is one possible mechanism to modulate the proliferative effect of Notch in the committed osteoblast progenitors which may be important in the pathogenesis of osteosarcomas. Therefore, understanding the functional interaction of miR-34 and Notch signaling in normal bone development and in bone cancer could potentially lead to therapies modulating miR-34 signaling.

MicroRNAs as regulators of bone homeostasis and bone metastasis

“…MiR-34c is an essential regulator of Notch signaling in osteoblasts, directly targeting Notch1, Notch2 and Jagged1, as well as Satb2 and Runx2. 30 Interestingly, miR-34c has been shown to function with both cell-autonomous and non-cell-autonomous activities. Although upregulation of miR-34c inhibits osteoblast differentiation by decreasing Satb2 and Runx2, the inhibition of Notch signaling might have a role in regulating the RANKL/OPG ratio, leading to increased osteoclast differentiation.…”

“…Although upregulation of miR-34c inhibits osteoblast differentiation by decreasing Satb2 and Runx2, the inhibition of Notch signaling might have a role in regulating the RANKL/OPG ratio, leading to increased osteoclast differentiation. 30,31 Thus, an individual miRNA is capable of simultaneously regulating multiple bone marrow cells to maintain homeostasis.…”

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

“…One such miRNA, miR-34c, is an essential regulator of Notch signaling in osteoblasts by directly targeting Notch1, Notch2 and Jagged1, as well as Satb2 and Runx2. 34 Interestingly, miR-34c has been shown to function with both cell-and non-cell-autonomous activities. Upregulation of miR-34c inhibits osteogenesis by decreasing Satb2 and Runx2 in osteoblasts, whereas inhibition of Notch signaling may regulate the RANKL/OPG ratio, leading to increased osteoclast differentiation.…”

“…Upregulation of miR-34c inhibits osteogenesis by decreasing Satb2 and Runx2 in osteoblasts, whereas inhibition of Notch signaling may regulate the RANKL/OPG ratio, leading to increased osteoclast differentiation. 34,35 Given the profound effect that regulated miRNA expression has on bone marrow cell differentiation and activity, it is perhaps not surprising that misregulation of miRNAs has also been linked to a number of bone-related pathologies, including miRNAs as biomarkers for bone metastasis progression A Aleč ković and Y Kang [36][37][38] and osteosarcoma. [39][40][41][42][43] Importantly, misregulated miRNAs have been proposed as potential biomarkers of the specific bone-related diseases as they may accurately reflect the disease state of the bone.…”

Realizing the potential of gene-based molecular therapies in bone repair

“…(72) The miRNA have recently been shown to regulate osteogenic commitment of mesenchymal stem cells. (73) The miRNAs can act as negative regulators of osteogenesis, (74)(75)(76)(77)(78)(79) or as promoters of osteoblast differentiation (Fig. 4).…”