Two is better than one
People with osteoarthritis have limited therapy options: painkillers or joint replacement surgery. A group from the Salk Institute for Biological Research found that a combination of two experimental drugs changes the cellular and molecular signs of osteoarthritis in rats, as well as in human cartilage cells in vitro.
Osteoarthritis is the most common joint disease in the United States, and its prevalence is expected to increase in the coming years due to an aging population and rising obesity. The disease is caused by gradual changes in cartilage in the joints. With aging and prolonged stress, the molecules and genes in the cells of the articular cartilage change, eventually leading to its destruction and the proliferation of the underlying bone. These changes cause chronic pain and restrict movement.
Previous studies have identified two molecules, alpha-KLOTHO and beta-receptor 2 transforming growth factor (TGFßR2), as potential agents for the treatment of osteoarthritis.
aKlotho acts on the molecules surrounding the articular cartilage cells, preserving this extracellular matrix from destruction.
TGFßR2 acts directly on cartilage cells, stimulating their proliferation and preventing their damage.
While each of these drugs showed moderate efficacy in osteoarthritis in animal models of the disease, the researchers suggested that the two drugs together would act more consistently.
The knee joint of a rat. The cartilage is painted white. The first picture is a healthy joint, the second picture is a joint with untreated osteoarthritis of the 2nd degree, the third picture is a joint with osteoarthritis, which worsened from the 2nd to the 4th degree after six weeks of placebo therapy. The lower figure shows a joint with osteoarthritis, which improved from grade 2 to grade 1 (mild) after six weeks of combined therapy with alphaKlotho and TGFbR2. Source: Salk Institute.
The researchers treated young rats with osteoarthritis with viral particles carrying DNA fragments with instructions for the synthesis of aKlotho and TGFßR2.
After six weeks, the rats who received placebo developed a more severe degree of osteoarthritis of the knee joints, the disease progressed from stage 2 to stage 4. The rats who received KLOTHO and TGFßR2 DNA demonstrated the restoration of articular cartilage: the tissue became denser, fewer cells died, and actively proliferating cells were present. The disease of these animals improved from stage 2 to a mild form of osteoarthritis, and no negative side effects were observed.
Further experiments revealed 136 genes that were more active and 18 genes that were less active in the cartilage cells of treated rats compared to control ones. Among them were genes involved in inflammation and immune responses, which indicates some mechanisms of action of the combined treatment.
To test the applicability of the drug combination for humans, the group treated human articular cartilage cells with aKlotho and TGFßR2 molecules in a laboratory dish. The levels of proteins involved in cell proliferation, extracellular matrix formation, and cartilage cell identity increased.
The results obtained are not enough to be applied in clinical practice, but this is a good sign that the combination can work for the treatment of patients.
The research team plans to further improve the method, including studying whether the soluble molecules of the proteins aKlotho and TGFßR2 can be taken directly, rather than injected through viral particles. They also plan to study whether a combination of drugs can have a preventive effect and prevent the development of osteoarthritis before symptoms appear.
Article by P.Martinez-Redondo et al. aKlotho and sTGFßR2 treatment counteract the osteoarthritic phenotype developed in a rat model is published in the journal Protein & Cell.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of SALK: Drug combo reverses arthritis in rats.