Nav: Home

Improved understanding of the pathology of dwarfism may lead to new treatment targets

December 12, 2018

Philadelphia, December 12, 2018 - Pseudoachondroplasia (PSACH) is a severe inherited dwarfing condition characterized by disproportionate short stature, joint laxity, pain, and early onset osteoarthritis. In PSACH, a genetic mutation leads to abnormal retention of cartilage oligomeric matrix protein (COMP) within the endoplasmic reticulum (ER) of cartilage-producing cells (chondrocytes), which interferes with function and cell viability. In a report in the American Journal of Pathology, investigators describe how this protein accumulation results in "ER stress" and initiates a host of pathologic changes. These findings may open up new ways to treat PSACH and other ER-stress-related conditions.

"This is the first study linking ER stress to midline 1 protein (MID1), a microtubule stabilizer that increases mammalian target of rapamycin complex 1 (mTORC1) signaling in chondrocytes and other cell types. This finding has significant implications for cellular functions including autophagy, protein synthesis, and potentially cellular viability. These results identify new therapeutic targets for this pathologic process in a wide spectrum of ER-stress disorders such as type 2 diabetes, Alzheimer disease, and tuberculosis," explained Karen L. Posey, PhD, Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.

PSACH symptoms generally are recognized beginning at two years of age. Patients with PSACH have normal intelligence and craniofacial features. PSACH is caused by mutations in the gene encoding the cartilage oligomeric matrix protein (COMP). ER stress occurs when abnormal (unfolded or misfolded) COMP (MT-COMP) accumulates in the rough endoplasmic reticulum of chondrocytes. Rough ER, the portion of ER displaying ribosomes, is the network of membranous tubules within cells associated with protein and lipid synthesis and export.

In previous studies, Dr. Posey and her colleagues have investigated chondrocyte pathology in the growth plates of dwarf mice that express MT-COMP, in cultured rat chondrosarcoma (RCS) cells that express human MT-COMP, as well as in cultured cartilage nodules from PSACH patients. The mice replicate many of the clinical features and chondrocyte pathology reported in patients with PSACH.

In the current study, the researchers showed increased levels of MID1 protein in chondrocytes from the mutant dwarf mice as well as in cells from human PSACH patients. They also found that ER-stress-inducing drugs increased MID1 signaling, although oxidative stress did not.

The up-regulation of MID1 was associated with increased mTORC1 signaling in the growth plates of the dwarf mice. Rapamycin decreased intracellular retention of MT-COMP and decreased mTORC1 signaling. The mTOR pathway is activated during various cellular processes (eg, tumor formation and angiogenesis, insulin resistance, adipogenesis, and T-lymphocyte activation) and is dysregulated in diseases such as cancer and type 2 diabetes.

The results of this work show that MID1, mTORC1 signaling, the microtubule network, protein synthesis, inflammation, and autophagy form a complex multifaceted response to protein accumulation in the ER when clearance efforts fail and MID1 may act as a pro-survival factor.

In this study, aspirin and resveratrol normalized levels of MID1 and mTORC1 signaling in growth plate chondrocytes from dwarf mice. The investigators therefore suggest that a combination of rapamycin with anti-inflammatory medications may be beneficial if side effects can be controlled.

"Our work identifies possible new treatment paths for PSACH, as well as other common conditions such as type 2 diabetes, Alzheimer disease, and cancer, all of which involve ER stress," added Dr. Posey. "We believe ER stress-reduction therapeutics will play an important role in the treatment of a wide variety of illnesses."
-end-


Elsevier

Related Diabetes Articles:

Tele-diabetes to manage new-onset diabetes during COVID-19 pandemic
Two new case studies highlight the use of tele-diabetes to manage new-onset type 1 diabetes in an adult and an infant during the COVID-19 pandemic.
Genetic profile may predict type 2 diabetes risk among women with gestational diabetes
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions.
Maternal gestational diabetes linked to diabetes in children
Children and youth of mothers who had gestational diabetes during pregnancy are at increased risk of diabetes themselves, according to new research published in CMAJ (Canadian Medical Association Journal).
Two diabetes medications don't slow progression of type 2 diabetes in youth
In youth with impaired glucose tolerance or recent-onset type 2 diabetes, neither initial treatment with long-acting insulin followed by the drug metformin, nor metformin alone preserved the body's ability to make insulin, according to results published online June 25 in Diabetes Care.
People with diabetes visit the dentist less frequently despite link between diabetes, oral health
Adults with diabetes are less likely to visit the dentist than people with prediabetes or without diabetes, finds a new study led by researchers at NYU Rory Meyers College of Nursing and East Carolina University's Brody School of Medicine.
Diabetes, but not diabetes drug, linked to poor pregnancy outcomes
New research indicates that pregnant women with pre-gestational diabetes who take metformin are at a higher risk for adverse pregnancy outcomes -- such as major birth defects and pregnancy loss -- than the general population, but their increased risk is not due to metformin but diabetes.
New oral diabetes drug shows promise in phase 3 trial for patients with type 1 diabetes
A University of Colorado Anschutz Medical Campus study finds sotagliflozin helps control glucose and reduces the need for insulin in patients with type 1 diabetes.
Can continuous glucose monitoring improve diabetes control in patients with type 1 diabetes who inject insulin
Two studies in the Jan. 24/31 issue of JAMA find that use of a sensor implanted under the skin that continuously monitors glucose levels resulted in improved levels in patients with type 1 diabetes who inject insulin multiple times a day, compared to conventional treatment.
Complications of type 2 diabetes affect quality of life, care can lead to diabetes burnout
T2D Lifestyle, a national survey by Health Union of more than 400 individuals experiencing type 2 diabetes (T2D), reveals that patients not only struggle with commonly understood complications, but also numerous lesser known ones that people do not associate with diabetes.
A better way to predict diabetes
An international team of researchers has discovered a simple, accurate new way to predict which women with gestational diabetes will develop type 2 diabetes after delivery.
More Diabetes News and Diabetes Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.