Discovery may explain why more females than males get knee osteoarthritis

New genetic research could lead to a blood test, better preventive strategies and even potential drug treatments.

By Gillian Rutherford, University of Alberta March 2, 2022

Female astronauts could avoid knee injuries during space flight — and better tests, prevention and treatments could be developed for knee osteoarthritis in women here on Earth — based on newly published research on the sex differences in knee meniscus tissue.

Knee osteoarthritis is more common in females than in males, but hormones alone are not enough to explain the difference. The new research identifies a genetic difference in the meniscus that makes about 50 per cent of females more vulnerable to developing osteoarthritis than males or other females.

Researchers carried out the experiments in part by simulating low-gravity conditions in space, which mimics the damage that can happen to the meniscus due to lack of exercise.

“Some of the genes that were found in the females that responded more to simulated space microgravity were also associated with the development of knee osteoarthritis,” said principal investigator Adetola Adesida, professor of surgery in the Faculty of Medicine & Dentistry.

The research suggests the potential for a blood test to identify who has the high-risk gene, allowing for early interventions such as physiotherapy, and eventually even drug therapy. It might also allow women to stay in space longer.

“We’ve uncovered the mechanisms that lead to this higher response, and we are hoping to develop drugs to target those pathways and block those responses,” Adesida said.

Use it or lose it

Meniscus is a kind of cartilage in the knee that acts as a load distributor for the body’s full weight. At one time, it was thought to be like the appendix: you wouldn’t miss it if it were gone. But now it’s known that just a small tear in the meniscus — usually caused by a sports injury — increases the risk of osteoarthritis later in life, even if the damaged tissue has been removed.

On the other hand, lack of use can also lead to deconditioning of the meniscus and increase arthritis risk. You’ll notice the short-term effect of deconditioning when you get out of bed in the morning and feel stiff, but then your joints loosen up once you’ve moved around for a while. It’s the same thing that happens to astronauts in space, unless they use specially designed resistance equipment to make up for the lack of weight-bearing exercise in microgravity.

Knee osteoarthritis is the most common joint problem, affecting an estimated 250 million people worldwide, including 14 per cent of females older than 60 and 10 per cent of males in the same age group. About 75,000 knee replacements were performed in Canada in 2019-20.

Out-of-this-world experiments

Adesida’s team has developed bioengineered meniscus tissue grown from cells that have been removed from the damaged menisci of otherwise healthy individuals. The hope is one day to be able to replace damaged tissue through transplant, preventing the development of knee osteoarthritis.

“The goal is really to be able to use a patient’s own cells to make a new meniscus for them,” Adesida explained.

This will help us to have human relevant models to study knee osteoarthritis in the future. And our research has both Earth benefits and space benefits. — Adetola Adesida

For their experiment on sex differences, the team studied how the bioengineered tissue functioned while at rest and under mechanical loading and unloading conditions. For the loading, they used a device that exerted hydrostatic pressure on the cells. For the unloading, they put the cells into a bioreactor designed by NASA to mimic minimal-gravity conditions.

They needed to do all this because it would not be ethical to just cut someone open to see what happens to their meniscus during exercise, a long hospital stay or a space flight, Adesida pointed out.

“Our loading and unloading experiment mimics what we actually see in a clinical situation where the development of spaceflight microgravity-induced knee osteoarthritic changes is possible,” he said.

“This will help us to have human relevant models to study knee osteoarthritis in the future. And our research has both Earth benefits and space benefits.”

Adetola Adesida runs the Adesida Laboratory of Cartilage Bioengineering and is director of the Orthopaedic Basic Science Research program within the department of surgery, associate director of the Otolaryngology Basic Science Research program and co-director of the ELITE Program for Black Youth at the U of A.

The research was a cross-disciplinary project co-led by Lindsey Westover, assistant professor in the Faculty of Engineering, and was funded by Natural Sciences and Engineering Research Council of Canada, Canadian Institutes of Health Research, Canada Foundation for Innovation, University Hospital Foundation, Cliff Lede Family Charitable Foundation, University of Alberta Pilot Seed Grant Program, and Alberta Women’s Health Foundation through the Women and Children’s Health Research Institute.

Source University of Alberta via Medical Xpress

References

Engineered Human Meniscus in Modeling Sex Differences of Knee Osteoarthritis in Vitro, Ma Zhiyao, Li David Xinzheyang, Kunze Melanie, Mulet-Sierra Aillette, Westover Lindsey, Adesida Adetola B. Front. Bioeng. Biotechnol. 15 February 2022. doi: 10.3389/fbioe.2022.823679. Full text

Further reading

Gender and Sex Are Key Determinants in Osteoarthritis Not Only Confounding Variables. A Systematic Review of Clinical Data, Tschon M, Contartese D, Pagani S, Borsari V, Fini M. J Clin Med. 2021 Jul 19;10(14):3178. doi: 10.3390/jcm10143178. Full text

Sex Specific Determinants in Osteoarthritis: A Systematic Review of Preclinical Studies, Contartese D, Tschon M, De Mattei M, Fini M. Int J Mol Sci. 2020 May 24;21(10):3696. doi: 10.3390/ijms21103696. Full text

Coculture of meniscus cells and mesenchymal stem cells in simulated microgravity, Weiss WM, Mulet-Sierra A, Kunze M, Jomha NM, Adesida AB. NPJ Microgravity. 2017 Nov 10;3:28. doi: 10.1038/s41526-017-0032-x. Full text

Matrix formation is enhanced in co-cultures of human meniscus cells with bone marrow stromal cells, Matthies NF, Mulet-Sierra A, Jomha NM, Adesida AB. J Tissue Eng Regen Med. 2013 Dec;7(12):965-73. doi: 10.1002/term.1489. Epub 2012 Mar 31.

Decreased hypertrophic differentiation accompanies enhanced matrix formation in co-cultures of outer meniscus cells with bone marrow mesenchymal stromal cells, Saliken DJ, Mulet-Sierra A, Jomha NM, Adesida AB. Arthritis Res Ther. 2012 Jun 22;14(3):R153. doi: 10.1186/ar3889. Full text

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