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Introduction: What they say

A study from Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany shows that “Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells.” This research paper was published, in the 17 July 2017 issue of the journal “Nature Medicine” [One of the best research journals in General Medicine with an I.Fs of 30.357], by Prof. Andreas Ramming, Rauber S and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that:  Mechanistic insights into how Zoledronate attenuates Arthritis: Zoledronate (also known as Zoledronic acid) (brand name: Reclast, Zometa and others), used to treat bone diseases, including osteoporosis, high blood calcium & bone breakdown due to cancer, and Paget’s disease of bone, increases IL-9 levels, augments proliferation of ILC2s (type 2 innate lymphoid cells) and regulatory T (Treg) cells, promotes resolution of inflammation, attenuates cartilage destruction, decreases bone loss, prevents fracture, and inhibits pathological features associated with arthritis, via up-regulation of its target genes

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From the significance of the study to Public health relevance:

Given that: (1) Rheumatoid arthritis (RA) has caused 49,000 deaths globally in 2010; and it is likely that death due to RA may increase in the coming years; (2) RA approximately affects between 0.5% to 1% of adults in the developing world; (3) between 5 and 50 per 100, 000 people develop RA each year; (3) Women are three to five times more affected by RA than men; (4) most of the drugs that are in use today, to treat RA, treats only the symptoms, not the root cause of the disease; (5) RA is characterized by chronic joint pains; and (6) the global economic cost spent in the treatment of RA is enormous, there is an urgent need to find: (i) molecular mechanisms and the components involved in bio-pathways leading to RA; (ii) a cheaper alternative to the existing expensive drugs; and (iii) a side-effect-free Natural product-based drug that alleviates not only Rheumatoid arthritis (RA) pain, but also cures RA.


What is known?

Prof.Andreas Ramming‘s research team has recently shown that: (1) interleukin (IL)-9-producing type 2 innate lymphoid cells (ILC2s) as mediators of chronic inflammation; (2) the lack of IL-9 production culminates in: (a) defective ILC2 proliferation and activation of regulatory T (Treg) cells; (b) arthritis; (c) excessive cartilage destruction; and (d) bone loss; (3) treatment with IL-9 results in a) resolution of inflammation; and b) protection of bone; and (4) increased numbers of IL-9+ILC2s in joints and the circulation of patients, in remission stage of rheumatoid arthritis, suggesting that IL-9-mediated ILC2 activation is a method of treatment for chronic inflammation, such as arthritis, as it promotes resolution of inflammation rather than suppression of inflammatory mediators.


From research findings to Therapeutic opportunity:

A study from the University of Aberdeen, Aberdeen, UK. has published the role of Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON)...” This study was published, in the 11 April 2019 issue of of the prestigious journal Lancet (Impact factor: 53+), by  Prof. Reid DM, and others.  This study suggests that a single infusion of Zoledronic acid prevents steroid (glucocorticoid)-induced osteoporosis.  

Earlier, a study from the Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, and the Auckland District Health Board, Auckland, New Zealand had published its research findings stating thatFracture Prevention with Zoledronate in Older Women with Osteopenia.” This study was published, in the 1 October 2018 issue of of the prestigious journal N Engl J Med. (NEJM) (Impact factor: 79.258+), by  Distinguished Prof. Reid IR, Horne AM and others.  This study suggests that Zoledronate (also known as Zoledronic acid ) prevents fractures in older women with osteopenia.  However, the precise mechanism of action of the widely used drug Zoledronate remains largely unclear. 

The study presented here substantiates and supports the aforementioned studies’ claim by providing detailed mechanistic insights into how  Zoledronic acid may protect against fracture and aid in attenuating Rheumatoid arthritis, osteoporosis and other inflammatory diseases.

 A pharmaceutical mixture encompassing Zoledronic acid  and Vitamin-D3 (Calcitriol/Cholecalciferol), which is commonly used to treat bone-related disorders, by increasing the expression of its target gene, it may increase the expression of IL-9 (Interleukin-9) and its down stream target genes (Figs. 1-2). Thereby, it may: (1) increase the proliferation of ILC2s cells; (2) promote activation of Treg cells; (3) promote resolution of inflammation; (4) suppress cartilage destruction; (5) inhibit bone loss and strengthen bone structure; and (6) inhibit arthritis progression (Figs 2-5).

Figure 1. Mechanistic insights into how a pharmaceutical mixture encompassing Zoledronic acid  & Vitamin-D3, by increasing the expression of its target genes, increases IL-9 levels, promotes proliferation/activation of ILC2s/Treg cells, enhances the resolution of inflammation, stifles cartilage destruction inhibits bone loss, and protects against fracture rheumatoid arthritis and osteoarthritis.

Figure 2.  A pharmaceutical mixture encompassing Zoledronate  and Vitamin-D3  may attenuate inflammation, and prevent fracture, rheumatoid/psoriatic arthritis and ulcerative colitis through up-regulation of IL-9

Figure 3. While it has been shown that activation of IL-9 producing type 2 innate lymphoid cells prevents inflammatory diseases, including rheumatoid arthritis, this study suggests for the first time that  a pharmaceutical mixture encompassing Zoledronic acid (Zoledroonate) and Vitamin-D3  may attenuate bone loss and prevent osteo/rheumatoid/psoriatic-arthritis and fracture through up-regulation of IL-9.

Figure 4. While it has been shown that Zoledronic acid(the study depicted in the fig.4 above) attenuate fracture,  the mechanism of action remains unclear. This study suggests, for the first time, a pharmaceutical mixture encompassing Zoledronic acid  and Vitamin-D3  prevents fracture, attenuates rheumatoid/psoriatic arthritis, and bone loss through up-regulation of IL-9.

Figure 5. While it has been shown that Zoledronic acid (the study depicted in the fig.5 above) attenuates fracture,  the mechanism of action remains unclear. This study suggests, for the first time, that a pharmaceutical mixture encompassing Zoledronic acid  and Vitamin-D3/Calciferol/Cholecalciferol attenuates rheumatoid/psoriatic arthritis and prevents fracture and bone loss  through up-regulation of IL-9.

Together, this study suggests that a pharmacological mixture encompassing Zoledronate (also known as Zoledronic acid) or its analogs”, either alone or in combination with other drugs, will: a) prevent fracture and bone loss in postmenopausal women; and b) attenuate the progression of rheumatoid/psoriatic  arthritis. 


Details of the research findings:

Idea Proposed/Formulated (with experimental evidence) by: Dr L Boominathan Ph.D.

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Amount: $1, 500#

Undisclosed mechanistic information: How Zoledronate increases IL-9 levels, activates ILC2 proliferation and regulatory T (Treg) cells, inhibits cartilage destruction, suppresses bone loss and improves arthritis.

# Research cooperation

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References:

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Citation: Boominathan, L., Mechanistic insights into how Zoledronate attenuates Arthritis: Zoledronate (also known as Zoledronic acid) (brand name: Reclast, Zometa and others), used to treat bone diseases, including osteoporosis, high blood calcium & bone breakdown due to cancer, and Paget’s disease of bone, increases IL-9 levels, augments proliferation of ILC2s (type 2 innate lymphoid cells) and regulatory T (Treg) cells, promotes resolution of inflammation, attenuates cartilage destruction, decreases bone loss, prevents fracture, and inhibits pathological features associated with arthritis, via up-regulation of its target genes, 17/August/2019, 6.12 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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