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BMP-9 Identified in Rare Disease Progression
United States: In a set of cell and animal experiments, a team has found out who is mainly to blame for worsening symptoms in patients suffering from fibrodysplasia ossificans progressiva, a rare hereditary disease.
The team was headed by CiRA’s Associate Professor Makoto Ikeya and the Owner of Chongqing Medical University, Cheng Chu Zhao, who is a former researcher at CiRA’s Department of Clinical Application. The results of their study are presented in the EMBO Molecular Medicine scientific journal.
A Rare and Complex Disease
Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary disease characterized by the fact that muscles and connective tissue are replaced by bone tissue due to a mutation in the gene encoding a bone morphogenetic protein (BMP) type I receptor in more than 95% of FOP patients, which leads to the activation of BMP signaling by Activin A, a TGF-β ligand, as reported by Medicalxpress.
This heterotopic ossification (HO) is peculiar to flare, which is episodes of painful soft tissue swelling that are traceable to a minor injury. Reno-activated FAPs, a mesenchymal stromal cell (MSC) population, give rise to most of the newly formed bone tissue associated with HO.
Consequently, any measure that would hamper the growth of the FAPs may slow down the progression of the disease. Nevertheless, the exact molecular pathways related to flare-ups are still not well understood.
Study Identifies Key Driver
In order to study the flare-up mechanisms in more detail, the research team initially aimed at defining molecules that might be associated with the stimulation of MSC proliferation in FOP patients. For this, they used a panel of potential ligands to treat FOP-iMSCs and resFOP-iMSCs, induced pluripotent stem cells derived from an FOP patient and detected with mutated or corrected ACVR1, respectively.
In terms of the effect on proliferation, most of the TGF-β and BMP ligands exhibited a similar trend on FOP- and resFOP-iMSCs, with the exception that BMP-9 stimulated the proliferation of FOP-iMSCs, an effect that was validated using a second set of iMSCs from another FOP patient. Other experiments which analyzed more for a cell proliferative marker and the ability of the FOP-iMSCs to progress through the cell cycle also provided significant evidence for a particular role of BMP-9 in FOP-iMSCs.
The researchers then investigated the in vivo function of BMP-9 by injecting it into the muscles of FOP model mice that possess the FOP mutation. Most notably, the intramuscular injection of BMP-9 caused changes in the tissue that mimicked flare-ups in regard to the formation of abnormal cartilage and bones as well as the uptick of FAP accumulation, but only in mice with expressed mutant ACVR1.
In order to learn more regarding the involvement of BMP-9 in FOP pathogenesis, the research group also performed experimental muscle damage by injecting cardiotoxin into the calf muscle of FOP model mice. Morphological analysis of the injury site demonstrated that proliferative BMP-9-positive cells and BMP-9-rich extracellular matrix in the surrounding area may contribute to the increase in serum BMP-9 levels.
On the other hand, the isoform used for the intramuscular cardiotoxin injection into healthy mice promoted the appearance of BMP-9-positive cells within the lesion area; however, their density seemed to decrease while muscle regeneration began, and there was also no significant change in serum BMP-9 levels. In addition, the authors pointed out that monocytes and macrophages, which constituted the first line of inflammation in the investigated FOP, were the major source of BMP-9 responsible for the ectopic FAP deposition in the subsequent phases of muscle damage and HO in the FOP model mice.
The researchers used genetic and pharmacologic analyses to establish the significant role of BMP-9 in HO of FOP and assess whether these results might have impacts as potential treatments for FOP. As in FOP model mice with a deletion of the BMP-9 gene or treated with a BMP-9 neutralizing antibody, HO progression following intramuscular cardiotoxin injection was reduced.
Moreover, the antibody-based BMP-9 neutralizing study indicated that BMP-9 is best neutralized in the early hours to curtail the progression of HO.
Potential Therapeutic Breakthroughs
Lastly, to know how BMP-9 induces FAP proliferation, the research team compared the gene expression of treated and untreated FOP- and resFOP-iMSCs. As anticipated, this analysis pointed towards an improvement in TGF-β signaling; this research also tested for TGF-β activation explicitly; it used techniques to test SMAD2/3 phosphorylation.
On the basis of these observations, the researchers used gain and loss of function studies to determine whether targeting ACVR1-SMAD signaling through genetic downregulation or pharmacological inhibition would inhibit FOP-iMSCs proliferation. From these experiments, they concluded that in BMP-9 stimulated FOP-iMSC, DMH1 small molecule that targets only the SMAD binding site in ACVR1 abrogated the proliferation; however, it had no effects on TGF-β stimulated FOP- and resFOP-iMSC, as reported by Medicalxpress.
Hope for FOP Patients
Moreover, they found that TGF-β signaling repressed the enhanced proliferation of FOP-iMSCs due to the genetic inhibition of SMAD2/3 by siRNA-mediated knockdown.
In carrying out this study, the research team showed the significant BMP-9-mediated MSC proliferation in flare-ups in patients with FOP. In addition, the researchers prove the therapeutic potential of several prospective approaches to prevent losses due to this detrimental signaling activates by BMP-9 so that the patients who suffer from FOP can expect some improvements in reducing the severity of flare-ups.
News
Nicotine Cap Could Expose Cigarettes’ True Danger
United States: The Biden administration is expected to officially put forward a limit to nicotine in cigarettes in the last days of its term. It would be an eleventh hour act to speak against the tobacco industry after Biden has still not solidify plans to enact a prior campaign promise of eradicating menthol cigarettes, as reported by NBC News.
A Last-Minute Push Against Tobacco Addiction
The plan, which may be unveiled as soon as this Monday, is not likely to include methods such as tobacco alternatives or vaping and nicotine gum, patches, and lozenges.
“This is a Hail Mary from the Biden administration to move forward with a meaningful proposal, or at least to jump-start one in the waning days of the administration,” said Erika Sward, assistant vice president of national advocacy for the American Lung Association.
The Hook Behind Smoking Addiction
The chemical compounds that lead to chronic diseases and death for smokers are those found in combustible tobacco, whereas nicotine is the addictive substance that initially engages the smoker and sustains the habit.
The specific measures regarding the proposed limits of nicotine have not been unveiled. Various researchers have it, however, that it may have to be reduced to as low as 5% for the product to be considered minimally or non-addictive.
“This would be a historic action by the FDA that has the potential to have an enormous impact on public health,” said Dr. Rose Marie Robertson, science and medical officer of the American Heart Association.
America’s Leading Preventable Health Threat
A vast majority of smokers have taken their first cigarette in their teenhood. The move to a lesser addictive cigarette, Sward said, would save millions of lives.
An academic analysis conducted by the Food and Drug Administration in 2018 showed that the cap on nicotine levels would lead to 16 million people not becoming smokers, to begin with, by 2060. According to that study, it would rise to 33.1 million by the year 2100 at the earliest level.
That means even if the Biden administration releases the proposed rule next week, it will probably be years before it becomes final.
Game-Changing Public Health Impact
Yolanda C. Richardson, president and CEO of the Campaign for Tobacco-Free Kids, told NBC News that limiting the amount of nicotine in cigarettes would be “game-changing.” Few initiatives would make a greater impact on combating chronic illnesses like cancer and heart disease, which significantly impair American health and that the next government has stated should be a top focus.
Before the FDA announced it was thinking about capping nicotine levels, which it has the right to do, it was during President-elect Donald Trump’s first term in office.
Challenges Ahead for the Proposed Rule
By announcing a “comprehensive plan” in 2017, then-FDA Commissioner Dr. Scott Gottlieb started the process by proposing to “regulate nicotine in combustible cigarettes and render them minimally or non-addictive.”
It was also designed, in part, to refocus adult smokers onto non-combustible products like e-cigarettes. The 2017 plan also envisaged regulation of e-cigarette flavors and a total ban on the use of menthol products. In 2020, the federal government approved a restriction on all popular flavors, although menthol is still available.
Adding to this, in an interview this week, Gottlieb stated that smoking prevalence would have to be “on the list of top priorities of any public health agenda geared towards reducing chronic diseases.”
“There could be perhaps no more impactful thing we can do than to dramatically reduce smoking rates in this country,” he said.
News
Is a Foreign Weapon Behind Havana Syndrome?
United States: The CIA and the Treasury Department do not believe a foreign power has caused the still-unexplained ailments that affected some U.S. diplomats and other officials while posted in Cuba, but two agencies now concede it is possible that an adversary might have developed or even used a weapon to produce the mysterious injuries, as reported by HealthDay.
The conclusion, which resembles the findings of the earlier probes, stems from a survey of seven intelligence bodies that analyzed the incidences of head impacts and other symptoms expressed by other American diplomats and various other military and governmental personnel who raised the concerns about involvement of a foreign competitor.
Intelligence Findings
The new assessment of the situation was unveiled by the U.S. intelligence on Friday. When assessing the data, five intelligence agencies stated that the external enemy’s participation is highly improbable, a U.S. intelligence official told reporters upon the briefing on condition of anonymity since it was the requirement of the Office of the Director of National Intelligence.
Two of the agencies, however, concluded that it could be that a foreign power might have developed, or perhaps used, a weapon that might have caused the injuries reported by the US diplomats and the government officials.
The Ongoing Mystery
Headaches, balance problems, and problems with thinking and sleeping were first reported in Cuba in 2016 and in hundreds of American personnel in several countries later in the year. American diplomats stationed in Havana were the first to complain, which prompted the sequence of maladies to be nicknamed Havana syndrome.
The two agencies, which officials did not name, failed to trace any of these events to a particular foreign technology but came to their conclusions through some understanding of foreign weapons systems development and capabilities. Finally, one of the agencies discovered that the probability was roughly even that a foreign government utilized such a weapon or prototype device in a small, unknown number of cases involving U.S. personnel.
The other agency concluded that although it might have been developed by another nation, it is still doubtful that it has ever been used.
The Biden Administration’s Response
The Biden administration has been under pressure to probe the incidents after the American staff complained of brain injuries and other symptoms after keeping getting attacked in what some call an attempt to attack and harm US personnel operating in a foreign land. However, till now, officials have not been able to pinpoint any one reason for such events.
Friday revelations issued are a variant of a ‘change in key judgments by some intelligence components’ and require further research, National Security Council spokesperson Sean Savett said in an email communiqué to journalists.
“Our focus on these priorities remains unwavering and must continue,” Savett said. “It is vital that the U.S. government continue critical research, investigate credible incidents, and strengthen efforts to provide timely care and long-term clinical follow-up.”
No Direct Evidence
The intelligence official who briefed reporters on Friday dismissed the shift, stating that the two agencies that left open the possibility that a foreign government was developing or deploying a weapon that caused the injuries had reported low confidence in their assessment, as reported by HealthDay.
The official admitted that other NSAs were more sure that foreign governments were not involved and that certain intelligence leads discovered by some of the U.S. intelligence raised doubts about foreign involvement.
“There’s no intelligence linking a foreign actor to any specific event,” the official told reporters.
News
Could Nicotine Caps End Smoking Addiction?
United States: More specifically, in the last days of its term, the current Biden government is speculated to formally offer a threshold on nicotine levels in cigarettes. It would probably be taken at the eleventh hour to counter the tobacco industry after President Joe Biden did not seal a long-standing promise to ban cigarettes containing menthol, as reported by NBC News.
A Last-Minute Push for Nicotine Regulation
The change will likely happen until next Monday and will not affect items such as tobacco products such as e-cigarettes or nicotine replacement patches and lozenges.
“This is a Hail Mary from the Biden administration to move forward with a meaningful proposal, or at least to jump-start one in the waning days of the administration,” said Erika Sward, assistant vice president of national advocacy for the American Lung Association.
Though people die and get sick from the poisonous chemicals produced by combustible tobacco, it is the nicotine that initially hooks smokers and sustains their addiction.
Details of the proposal for reducing the levels of nicotine have not been disclosed comprehensively. It was not the end of the year, though, when numerous studies have pointed out that, to achieve the compounds minimally or non-addictively, dosage may have to be reduced by almost 95 percent.
The Impact of Nicotine Reduction
“This would be a historic action by the FDA that has the potential to have an enormous impact on public health,” said Dr. Rose Marie Robertson, science and medical officer of the American Heart Association.
Tobacco use itself is the number one cause of preventable disease and death in the United States, based on the CDC, resulting in more than 480,000 deaths per year.
Data indicated that the majority of smokers began the habit when they were teenagers. Sward said that any process that could make cigarettes less appealing, less enjoyable, or less satisfying would save millions of lives.
An FDA study carried out in 2018 found that a nicotine cap would reduce smoking addiction cases to 16 million people in the year 2060. It would rise to 33.1 million in 2100, based on the study’s estimate.
Even if the Biden administration issues the proposed rule early next week, it may take several years to become final.
Yolonda C. Richardson, president and CEO of the Campaign for Tobacco-Free Kids, told NBC News that limiting the amount of nicotine in cigarettes would be “game-changing.” Few initiatives would make a greater impact on combating chronic illnesses like cancer and heart disease, which significantly impair American health and that the next government has stated should be a top focus.
The first time the FDA weighed in on limits on nicotine was during President-elect Donald Trump’s first term in office.
A Decade in the Making
In 2017,then-FDA Commissioner Dr.Scott Gottlieb kick-started the process with a “comprehensive plan,” of which one proposal was to “regulate nicotine in combustible cigarettes and make it minimally or nonaddictive.”
It was meant, in part, to move adult smokers to less hazardous products like vapor cigarettes or e-cigarettes. The 2017 plan also contained the prospect of integrating the regulation of e-cigarette flavors and a complete prohibition on the use of menthol products. A federal rule to eliminate most flavored e-cigarettes in 2020, but they now come in menthol flavor, as reported by NBC News.
This week, in an interview with Gottlieb, he was of the opinion that smoking incidence would necessarily have to be on the list of activities, which needed focus to enhance the health standards of people with chronic diseases.
“There could be perhaps no more impactful thing we can do than to dramatically reduce smoking rates in this country,” he said.
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