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Terence D. Capellini has been interested in how joints work for almost 30 years. Part of this is due to my personal experience as a college ice hockey player who suffered several joint injuries and recently developed knee osteoarthritis. However, principal investigators at Harvard’s Department of Developmental and Evolutionary Genetics have also identified similar diagnoses and injured loved ones’ pain and limited mobility.

“We have all these joints in our bodies and they don’t look the same to each other,” said Capellini, associate professor Richard B. Wolff of the Department of Human Evolutionary Biology. “Two very interesting interrelated questions are: Why do certain joints spontaneously develop some illness, but others do not? And some joints do not. Why are you more likely to get injured than other joints? “

These types of questions, along with a passion for understanding the skeleton, motivated Capellini to lead a study on joint disorders published on Tuesday. Nature Communications.. The results of this treatise could one day lead to treatments for two difficult-to-treat joint disorders that primarily affect the oldest and youngest populations in the world.

The report details a regulatory variant found near a gene called GDF5 that plays an important role in joint formation.This study identifies two separate mutations near the gene, one of which may be the cause Osteoarthritis of the knee In the elderly and in other adults who can cause hip dysplasia in infants. Knee osteoarthritis, knee Joints affect more than 30% of people over the age of 65, but hip dysplasia, a structural hip disorder, is found in one in 1,000 newborns.

Findings can lay the foundation for possible screening of these diseases and may allow medical and non-medical interventions because patients know they are at risk. There is. Results can also lead to the creation of potential therapies, as scientists can better understand, target, and possibly influence the expression of gene mutations to prevent disease.

“You can start to understand if you can start targeting these genetic regions for treatment,” Capellini said.

The researchers say that the mutations that lead to the disease occur within two different regulatory switches near the GDF5 gene. One of the switches affects the population of cells that form the knee joint into its shape, and the other affects the cells that properly fit the bone that grows around the hip joint. 

“These switches can be thought of as similar to the switches in a home lamp, where the light bulb is a gene,” Capellini said. “Each room may have the same 100 watt light bulb, but the kitchen switch turns on only the kitchen light bulb and the living room switch Turn it on only in the living room. “

This finding provides researchers with clues as to the biological importance of these switches as therapeutic target areas, as these switches are prone to destruction.

This report is a collaboration between Harvard University of Arts and Sciences, Broad Institute, Harvard Dental School, Harvard Medical School, Boston Children’s Hospital scientists and Chinese medical researchers. Pushpanathan Muthuirulan, a researcher in Capellini’s lab, was the first author of the study, and Ata Kiapour, an assistant professor of orthopedics at HMS and Children’s Hospital, did most of the medical imaging.

The research team started by examining the data obtained from Genome-wide association study About knee osteoarthritis and hip dysplasia. The goal of these types of research is to detect and map genetic mutations throughout the genome that are associated with disease risk and trait changes. They chose the GDF5 gene. This is because the GDF5 gene is a region of the genome associated with about 20 different skeletal properties, with mutations that cause hundreds of potential diseases.

Capellini and his colleagues have identified a genome-wide regulation on / off switch that is responsible for building various joints in the human body, including hips, knees, shoulders, and elbows. Using that information and relevant data from the entire genome, CRISPR gene editing techniques are used to modify human chondrocytes in the dish and manipulate mice to separate each of the found knee and hip switches. I gave it a mutation.

These humanized mouse models allowed researchers to study how each mutation affects the formation and pathology of each joint. They were able to determine whether the DNA sequences of these switches carry genetic mutations associated with the risk of knee osteoarthritis or hip dysplasia. Through the process of removal and painstaking functional testing, they discovered two separate mutations that could lead to both illnesses.

Researchers have also applied similar calculations to genes other than GDF5. They switch on and off different joints, with nearly three-quarters of the tested genes involved in multiple musculoskeletal diseases showing the same pattern among mutations that cause potential disease. I found it to separate.

The next step for researchers is to apply these experimental techniques to other regions of the genome to see if these patterns apply to knee osteoarthritis, hip dysplasia, and other skeletal disorders. In addition, we will continue to expand our research.

“On a broader scale, the risk of osteoarthritis and hip dysplasia is not due to just one mutation in one region of the genome, so we want to investigate more in all other regions of the genome,” says Capellini. It was. “Because this is a complex polygene trait, many regions of the genome pose a risk. Hip dysplasia Or osteoarthritis.I want to be able to start these modeling mutation In a more complicated way ”