A novel miR17 /protein tyrosine phosphatase-oc/EphA4 regulatory axis of osteoclast activity

Abstract

Information about the molecular mechanisms leading to the activation of the osteoclast is relatively limited. While there is compelling evidence that the signaling mechanisms of Src and integrin β3 are essential for osteoclast activation, the regulation of these two signaling mechanisms is not fully understood. In this review, evidence supporting a novel regulatory axis of osteoclast activation that plays an upstream regulatory role in both the Src and integrin β3 signaling during osteoclast activation is discussed. This regulatory axis contains three unique components: a structurally unique transmembrane protein-tyrosine phosphatase, PTP-oc, EphA4, and miR17. In the first component, PTP-oc activates the Src signaling through dephosphorylation of the inhibitory tyr-527 of Src. This in turn activates the integrin β3 signaling, enhances the JNK2/NFκB signaling, promotes the ITAM/Syk signaling, and suppresses the ITIM/Shp1 signaling; the consequence of which is activation of the osteoclast. In the second component, EphA4 inhibits osteoclast activity by suppressing the integrin β3 signaling. PTP-oc relieves the suppressive actions of EphA4 by directly dephosphorylating EphA4. In the third component, PTP-oc expression is negatively regulated by miR17. Accordingly, suppression of miR17 during osteoclast activation upregulates the PTP-oc signaling and suppresses the EphA4 signaling, resulting in the activation of the osteoclast. This regulatory axis is unique, in that each of the three components acts to exert suppressive action on their respective immediate downstream inhibitory step. Because the final downstream event is the EphA4-mediated inhibition of osteoclast activation, the overall effect of this mechanism is the stimulation of osteoclast activity.

miRNAs in osteoclast biology

“…These authors also found that miR-128 specifically targets Sirt1 mRNA post-transcriptionally. Downregulation of miR-17 activates bone resorption by stabilizing protein tyrosine phosphatase receptor type O (Ptp-oc or Ptpro) mRNA and thereby downregulating EPHA4 receptor signaling, indicating the involvement in coupling [96]. Further, downregulation of miR-155 inhibits bone resorption [97], while upregulation of miR-106b inhibits bone resorption [98].…”

Phosphorylation of the phosphatase PTPROt at Tyr 399 is a molecular switch that controls osteoclast activity and bone mass in vivo

“…In agreement, transgenic mice that overexpress PTPROt in their OCLs exhibit a male-specific decrease in bone mass (29). Molecularly, PTPROt has been reported to activate Src in these systems by dephosphorylating the kinase at Tyr 527 (by chicken Src numbering) (27)(28)(29), thus stimulating downstream signaling events such as signaling by integrin 3, the kinase Syk, and Jun N-terminal kinase and nuclear factor B (30,31).…”

Involvement of Noncoding RNAs in the Differentiation of Osteoclasts

“…Upregulation of miR-29 is implicated in cytoskeletal organization-involved cell migration by targeting CDC42 and SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2), a negative regulator of Rac1 [ 129 ]. Downregulation of miR-17 is reported to increase the fusion of osteoclasts possibly via the miR-17-protein-tyrosine phosphatase- (PTP-) EphA4 axis or directly targeting vav guanine nucleotide exchange factor 3 (Vav3), thus promoting ITGB3-dependent Vav3-mediated activation of Rac1/Rac2 [ 140 ].…”

“…Downregulation of miR-17 elevates c-Src activation by targeting PTP, which dephosphorylates the inhibitory pY527 of c-Src to activate c-Src signaling. miR-20 and miR-92, which are also members of the miR-17~92 cluster genes, also have potential target sites on PTP mRNA, indicating the 13 Stem Cells International possibility that they play similar negative regulation roles in osteoclastogenesis to that of miR-17 [140,155].…”