Conditional Disruption of <i>miR17∼92</i> in Osteoclasts Led to Activation of Osteoclasts and Loss of Trabecular Bone in Part Through Suppression of the <i>miR17</i>‐Mediated Downregulation of Protein‐Tyrosine Phosphatase‐oc in Mice

Lau, K.-H. William; Stiffel, Virginia M.; Rundle, Charles H.; Amoui, Mehran; Tapia, Jordan; White, Tyler D; Sheng, Matilda H.‐C.

doi:10.1002/jbm4.10014

Cited by 5 publications

(16 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The potential role of miR17 in the regulation of PTP-oc in osteoclastic cells was recently investigated (28), because the expression of a structurally-related PTP (PTPRO) was shown to be negatively regulated by miR17 (100). The miR17 is expressed as one of the six cluster genes of miR17~92 (i.e., miR17 , miR18 , miR19a , miR19b , miR20 , and miR92 ).…”

Section: Regulatory Roles Of Mir17~92 In the Ptp-oc-mediated Osteoclamentioning

confidence: 99%

“…The miR17 is expressed as one of the six cluster genes of miR17~92 (i.e., miR17 , miR18 , miR19a , miR19b , miR20 , and miR92 ). The in vivo evidence that miR17~92 is a negative regulator of osteoclast functions came from the characterization of the miR17~92 osteoclast conditional knockout mice (28), in that the miR17~92 conditional knockout mutants had highly active osteoclasts and lost substantial trabecular bone associated with marked increase in bone resorption, but without an effect on bone formation parameters.…”

Section: Regulatory Roles Of Mir17~92 In the Ptp-oc-mediated Osteoclamentioning

confidence: 99%

“…There are several strong pieces of in vitro evidence supporting the premise that the PTP-oc expression in osteoclasts is regulated in part by miR17 (28): First, an online search with the Targetscan database for potential miRNA target sequences has identified a highly conserved target site for miR17 on the 3′UTR of the PTP-oc mRNA, and the presence of the miR17 target site was confirmed by a miRNA target reporter assay (28). Second, the RANKL-induced osteoclast differentiation upregulated PTP-oc expression with a corresponding time-dependent downregulation of miR17 , and there was an inverse correlation between the levels of miR17 and the levels of PTP-oc mRNA in osteoclasts (28).…”

Section: Regulatory Roles Of Mir17~92 In the Ptp-oc-mediated Osteoclamentioning

confidence: 99%

“…Second, the RANKL-induced osteoclast differentiation upregulated PTP-oc expression with a corresponding time-dependent downregulation of miR17 , and there was an inverse correlation between the levels of miR17 and the levels of PTP-oc mRNA in osteoclasts (28). Third, the suppression of miR17 activity with an anti- miR17-5p locked nucleic acid (LNA) oligonucleotide, but not the suppression of miR19a activity with an anti- miR19a-5p LNA oligonucleotide, increased the cell size and the number of nuclei of osteoclasts, which are indices of activated osteoclasts (28). Fourth, the same resorption activators [i.e., IL-1 and 1,25(OH) 2 D 3 but not IL-6 and TNFα] that increased cellular PTP-oc mRNA and protein levels (21,22) also reduced the cellular miR17 level in osteoclasts (28).…”

Section: Regulatory Roles Of Mir17~92 In the Ptp-oc-mediated Osteoclamentioning

confidence: 99%

“…Intriguingly, PTP-oc also acts directly on EphA4 to suppress its forward signaling (26), which is a negative regulator of the osteoclast activity through inhibition of the integrin β 3 signaling (27), resulting in further enhancement in the osteoclast activity. The PTP-oc expression in osteoclasts is determined by post-transcriptional regulation in part through miR17 (28). Consequently, it appears that the miR17 , the PTP-oc, and the EphA4 represent three novel upstream regulators of the Src and integrin β 3 signaling in osteoclasts.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

Lau

Sheng

2018

Archives of Biochemistry and Biophysics

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Regulatory Roles Of Mir17~92 In the Ptp-oc-mediated Osteoclamentioning

confidence: 99%

Section: Regulatory Roles Of Mir17~92 In the Ptp-oc-mediated Osteoclamentioning

confidence: 99%

Section: Regulatory Roles Of Mir17~92 In the Ptp-oc-mediated Osteoclamentioning

confidence: 99%

Section: Regulatory Roles Of Mir17~92 In the Ptp-oc-mediated Osteoclamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Lau

Sheng

2018

Archives of Biochemistry and Biophysics

Self Cite

View full text Add to dashboard Cite

show abstract

The roles of protein tyrosine phosphatases in bone-resorbing osteoclasts

Shalev

Elson

2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

View full text Add to dashboard Cite

Maintaining the proper balance between osteoblast-mediated production of bone and its degradation by osteoclasts is essential for health. Osteoclasts are giant phagocytic cells that are formed by fusion of monocyte-macrophage precursor cells; mature osteoclasts adhere to bone tightly and secrete protons and proteases that degrade its matrix. Phosphorylation of tyrosine residues in proteins, which is regulated by the biochemically-antagonistic activities of protein tyrosine kinases and protein tyrosine phosphatases (PTPs), is central in regulating the production of osteoclasts and their bone-resorbing activity. Here we review the roles of individual PTPs of the classical and dual-specificity sub-families that are known to support these processes (SHP2, cyt-PTPe, PTPRO, PTP-PEST, CD45) or to inhibit them (SHP1, PTEN, MKP1). Characterizing the functions of PTPs in osteoclasts is essential for complete molecular level understanding of bone resorption and for designing novel therapeutic approaches for treating bone disease.

show abstract

miR17~92 is essential for the survival of hematopoietic stem and progenitor cells by restraining pro-apoptotic BIM

Brinkmann

Hyland

Graaf

et al. 2018

Preprint

View full text Add to dashboard Cite

SummaryThe micro RNA cluster miR17~92, also known as oncomiR-1, impacts diverse cellular processes, such as cell survival and proliferation. Constitutive loss of miR17~92 in mice causes severe defects in skeletal development, organ development and hematopoiesis, resulting in early post-natal lethality. The critical functions of miR17~92 in a fully developed animal have not yet been explored. Here we show that deletion of miR17~92 in adult mice had no impact on their lifespan or general well-being. However, detailed analysis of the hematopoietic system in mice, revealed a dramatic reduction in all mature hematopoietic lineages, which was due to the loss of early hematopoietic stem/progenitor cells (HSPCs). Strikingly, the concomitant loss of the pro-apoptotic BH3-only protein BIM rescued the loss of the HSPCs and all of their differentiated progeny that was caused by the deletion of miR17~92. These findings demonstrate that miR17~92 is critical for the survival of HSPCs by restraining the activity of the pro-apoptotic BH3-only protein BIM.

show abstract

Conditional Disruption of miR17∼92 in Osteoclasts Led to Activation of Osteoclasts and Loss of Trabecular Bone in Part Through Suppression of the miR17‐Mediated Downregulation of Protein‐Tyrosine Phosphatase‐oc in Mice

Cited by 5 publications

References 40 publications

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

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

The roles of protein tyrosine phosphatases in bone-resorbing osteoclasts

miR17~92 is essential for the survival of hematopoietic stem and progenitor cells by restraining pro-apoptotic BIM

Contact Info

Product

Resources

About