Periodic Reporting for period 1 - C.A.R.E. OA (Cross-linking Adenosine Receptors - Estrogen receptors for OA treatment)
Berichtszeitraum: 2021-02-25 bis 2023-02-24
Osteoarthritis (OA) is a common rheumatic disease that affects more than 30 million people worldwide, a number that will continue to rise in the coming decades due to the increased life expectancy and increased prevalence of obesity in the population.
There is no cure for OA and the treatments to manage the symptoms, pharmacological and non-pharmacological therapies, are useful only for a limited time, after which joint replacement is necessary.
Women have an increased risk of developing OA compared to men, and the risk rises after menopause, when the level of the female sex hormone estradiol decreases.
Normal joint function is maintained by many different cells and molecules. A molecule that plays an important role in the healthy function of the joint is adenosine. It has been shown that adenosine signaling can be affected by estradiol in certain types of cells, but it is still unclear whether this can happen in T cells, a cell type in the immune system that contributes to increased inflammation in OA. The purpose of the study was to investigate whether estradiol can regulate the function of adenosine in T cells and thus reduce inflammation in the joints, as well as to evaluate whether regulation of estradiol and adenosine interactions can be used as a treatment for OA.
The project was implemented following 3 objectives:
• Training objective: To enhance professional skills and become a research leader;
• Research objective 1: To test the hypothesis that estradiol modulates the expression and function of the adenosine receptors in T cells;
• Research objective 2: To determine if combined treatment with estradiol and a modulator of the adenosine signaling reduces the disease progression in an OA mouse model.
There is no cure for OA and the treatments to manage the symptoms, pharmacological and non-pharmacological therapies, are useful only for a limited time, after which joint replacement is necessary.
Women have an increased risk of developing OA compared to men, and the risk rises after menopause, when the level of the female sex hormone estradiol decreases.
Normal joint function is maintained by many different cells and molecules. A molecule that plays an important role in the healthy function of the joint is adenosine. It has been shown that adenosine signaling can be affected by estradiol in certain types of cells, but it is still unclear whether this can happen in T cells, a cell type in the immune system that contributes to increased inflammation in OA. The purpose of the study was to investigate whether estradiol can regulate the function of adenosine in T cells and thus reduce inflammation in the joints, as well as to evaluate whether regulation of estradiol and adenosine interactions can be used as a treatment for OA.
The project was implemented following 3 objectives:
• Training objective: To enhance professional skills and become a research leader;
• Research objective 1: To test the hypothesis that estradiol modulates the expression and function of the adenosine receptors in T cells;
• Research objective 2: To determine if combined treatment with estradiol and a modulator of the adenosine signaling reduces the disease progression in an OA mouse model.
The purpose of one of the research objectives was to test the hypothesis that combining treatment with a modulator of the adenosine signaling and estradiol is an effective strategy against disease progression in an OA mouse model.
A pilot study was performed to find the proper dose of estradiol able to mimic the physiological concentration of the steroid hormone without important side effects in the whole body. For this purpose, ovaries were removed from female mice (OVX mice) to lower the endogenous level of sex hormones. Then, two doses of estradiol were administered every 3 days for 8 weeks and the effect of the hormone in different organs was measured every 2 weeks. The dose of estradiol resembling the physiological level of the hormone on bone was chosen for the following experiments. Data from the pilot study were shared with the scientific community through a peer-review publication and an open-access repository.
The effect of ovary removal and subsequent reduction of sex hormones was tested on an OA mouse model. Data shows that estradiol replacement in OVX mice reduces cartilage and bone damage, lower joint inflammation, and improves motor ability and pain sensitivity. Moreover, the number of T cells in the inguinal lymph nodes, which drains the knee, decreased in OVX mice treated with estradiol. These results were presented at the 2022 OARSI World Congress on Osteoarthritis (Berlin, 6-10 April 2022) and published on a peer-reviewed journal.
In the latest experiment, I tested the effect of a modulator of the adenosine signaling on OVX and control OA mice after 8 and 12 weeks of treatment. Data have been collected and a manuscript is in preparation.
The study of the molecular interaction of estradiol-adenosine signaling in T cells is ongoing.
The implementation of the project together with the participation in meetings and training courses allow me to acquire technical abilities, pedagogical knowledge, and leadership skills.
A pilot study was performed to find the proper dose of estradiol able to mimic the physiological concentration of the steroid hormone without important side effects in the whole body. For this purpose, ovaries were removed from female mice (OVX mice) to lower the endogenous level of sex hormones. Then, two doses of estradiol were administered every 3 days for 8 weeks and the effect of the hormone in different organs was measured every 2 weeks. The dose of estradiol resembling the physiological level of the hormone on bone was chosen for the following experiments. Data from the pilot study were shared with the scientific community through a peer-review publication and an open-access repository.
The effect of ovary removal and subsequent reduction of sex hormones was tested on an OA mouse model. Data shows that estradiol replacement in OVX mice reduces cartilage and bone damage, lower joint inflammation, and improves motor ability and pain sensitivity. Moreover, the number of T cells in the inguinal lymph nodes, which drains the knee, decreased in OVX mice treated with estradiol. These results were presented at the 2022 OARSI World Congress on Osteoarthritis (Berlin, 6-10 April 2022) and published on a peer-reviewed journal.
In the latest experiment, I tested the effect of a modulator of the adenosine signaling on OVX and control OA mice after 8 and 12 weeks of treatment. Data have been collected and a manuscript is in preparation.
The study of the molecular interaction of estradiol-adenosine signaling in T cells is ongoing.
The implementation of the project together with the participation in meetings and training courses allow me to acquire technical abilities, pedagogical knowledge, and leadership skills.
OA is one of the most common conditions among rheumatic diseases. Pain, loss of joint function and mobility, social isolation, and a broadly reduced quality of life underscores the high medical and social impact of OA. In Europe, the annual cost for each patient ranges between €1330 and €10452, representing a huge burden that is expected to rise substantially further with the aging population and increase in obesity rate (weight bearing and mild chronic inflammation).
Post-menopausal women have an increased risk of developing OA compared to men. in this study we aimed to clarify whether estradiol-mediated regulation of adenosine receptors can be utilized for the development of new treatments for patients with OA.
We expect that the outcome of this analysis will lead to new and sex-specific treatments and prevention actions necessary to improve the life quality of women and reduce societal costs.
Post-menopausal women have an increased risk of developing OA compared to men. in this study we aimed to clarify whether estradiol-mediated regulation of adenosine receptors can be utilized for the development of new treatments for patients with OA.
We expect that the outcome of this analysis will lead to new and sex-specific treatments and prevention actions necessary to improve the life quality of women and reduce societal costs.