Micro-RNAs is the future of bone defect repair – An Overshadowed Work Worthy of Winning The Nobel Prize

As new technology allows researchers to plunge deeper into the genome, a new class of RNA called micro RNA may play an intriguing role. Repairing bone defects may get easier thanks to newly discovered micro RNAs claims a study done at the University of Münster.

These researches might help in meeting the increasing demand resulting from the high incidence of large segmental bone defects due to trauma, congenital malformations, ageing, or bone-related diseases such as osteoporosis, inflammation or tumors.

Similarities are being drawn between the study of Bruce Beulter’s nobel prize winning work. The depth and intensity of this exciting area of MiRNAs research has been far beyond many new frontiers, such as, for example, the Toll receptors, about which Bruce Beulter, received the Nobel Prize.

The nobel prize winner has overshadowed the works of Peter M WONG claiming superiority over the latter.  But the facts speak otherwise.  Wong et al  used a novel method of creating a retroviral cDNA library to fish out a gene by function – Ran GTPase – and showed that mutations at the 3′-UTR could be used to modulate host innate immune response to endotoxin challenge.   His review in J Biolmedical Science 2003; 10: 468-474, on Ran GTPase suggests their discoveries will have vast medical applications, potentially from treating endotoxic shock, arthritis, to cancer – anything requiring up- or down-modulation of host immune response.

We spoke to Peter M WONG regarding the matter. Peter M WONG states that:

“Our works on this subject matter were published several times in first tier scientific journals, such as ProcNatAcadSci, JBiolChem, MolCellBiol, JVirol, Inf Immunity.  In fact, our first work was submitted to Nature; it was conditionally accepted initially in 1996, and was later rejected.  Afterwards, Nature published a lead comprehensive review article on the biology of 3′-UTRs, sadly, without acknowledging our work.  Also, I was an invited Speaker to International Endotoxin Society at Pasteur Institute in Paris back in 2000, as well as many other US DoD DARPA meetings since 1995, and a number of national and international scientific meetings.  The editor of ScientificWorld J wrote me our review on Ran GTPase medical applications was the top download and they wanted me to write another one, which I could not because of the international attentions I had been intensely receiving.

Peter M WONG continues fearlessly…

“Sadly, strangely, and disappointingly, bad politics, real bad dirty politics prevail.  Despite all the attention I had been receiving, our work never got cited much officially, which was outrageously ridiculous.  Many review articles did not even mentioned our work. And subsequently, all my grant applications received absurd critiques, and the locally environment became toxic.  My research came to a halt.  The miRNA and 3′-UTR started to explode and the specific area of Ran GTPase in immune response remains untouched to this date, although almost all Ran’s associated molecules since then started to receive a great deal more of attention especially in terms of potential medical applications.  Again, none that I know mentioned our work; as well, Ran GTPase, conspicuously, was never or indirectly mentioned  – a big shift from Ran being a STAR in the assembly molecules of nuclear transport.  Obviously, the bad politics has been at the very high level.“

Regardless of the controversy surrounding this groundbreaking research, it opens new frontiers in tissue engineering.  Delivery of miRNAs may provide a way to maximally mimic the native bone development environment, and thus possess the therapeutic potential to enhance bone regeneration and repair.

Bone formation and regeneration is a multistep complex process crucially determined by the formation of blood vessels in the growth plate region. This is preceded by the expression of growth factors, notably the vascular endothelial growth factor (VEGF), secreted by osteogenic cells, as well as the corresponding response of endothelial cells, although the exact mechanisms remain to be clarified. Thereby, coordinated coupling between osteogenesis and angiogenesis is initiated and sustained. The precise interplay of these two fundamental processes is crucial during times of rapid bone growth or fracture repair in adults. Deviations in this balance might lead to pathologic conditions such as osteoarthritis and ectopic bone formation.

Leopold F. Fröhlich emphasizes that besides VEGF, the recently discovered important regulatory and modifying functions of microRNAs also support this key mechanism. These comprise of  two principal categories of microRNAs that were identified with specific functions in bone formation (osteomiRs) and/or angiogenesis (angiomiRs).  Hypoxia is considered  a major driving force behind bone angiogenesis. So a third group involved in this process is represented by hypoxia-inducible microRNAs (hypoxamiRs).

The explosion of miRNA discoveries, to a very large extent, was triggered by Wong’s discoveries in Ran GTPase since 1996.  Their studies showed that a SINGLE POINT MUTATION IN THE 3′-UTR of RAN GTPase led to profound changes in RNA structure, mRNA localization, Ran’s nuclear/cytoplasmic ratio, of key pro-inflammatory cytokine levels, and the response of treated animals against endotoxin challange and other microbial infections.  

This series of studies by Wong et al bear important features: (1) The importance of single-point mutation in disease development has precedence:  A change in amino acid at position 6 of a subunit of hemoglobin produces Sickle Cell Anemia.  Linus Pauling received Nobel Prize because of it.  (2) The mutation at 3′-UTR, a non-protein region, is even more intriguing.  It points to new importance in biological regulations and medical applications, as the studies show mutations result in corresponding changes in RNA structure, localization, etc – all about post-translational regulation, pointing to the presence of “zip-code” motifs found in basic research in lower vertebrates. These changes also lead to profound biological changes with medical applications, hence engendering great enthusiasm in the search for miRNAs, and hence reviews by Leopold F Frohlich and many others.  (3)  Because the studies show that Ran GTPase can be applied to modulate host immune response, via controlling a molecule – NFkB – well known to play a vital role in the regulation of host immune responses, it will have vast medical applications much beyond endotoxic response.  Finally, (4) the totally novel strategy of creating a retroviral cDNA library to fish for relevant gene(s) by function is very powerful.   Since our publication, Yamanaka et al adopted this strategy, showed that 4 specific genes are important in the reprogramming of converting fibroblasts to immature stem cells and received the Nobel Prize because of it.

Published in  the Journal Cells in the January 2019 issue, this study highlights the gargantuan medical impact of MicroRNA, or miRNA – much of it stems from motifs in 3′-UTRs (3′-UnTranslated Region of mRNA).  The  review  focused on the identification of microRNAs that were found to have an active role in osteogenesis as well as angiogenesis to date that were termed “Coupling miRs (CPLGmiRs)”.  MicroRNAs that already had been associated with an active role in osteogenic-angiogenic coupling or  presumed to have its potential were chosen as representatives.

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