Prevention of pathological bone remodeling with paroxetine (DMM + Px) in osteoarthritis in mice
Carlson et al. / Science Translational Medicine, 2021
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American scientists have come to the conclusion that the antidepressant paroxetine can stop and even partially reverse the destruction of cartilage in osteoarthritis, thus affecting the course of the disease. The drugs used now only deal with its symptoms. Results of work published
in the journal Science Translational Medicine.
Osteoarthritis is the most common joint disorder that suffers every thirtieth inhabitant of the Earth. It occurs due to the gradual wear of the articular cartilage with age or after injury, which is accompanied by inflammation. The currently used anti-inflammatory therapy reduces the symptoms of the disease, but practically does not slow down the destruction of cartilage, due to which, sooner or later, there is a need for joint replacement.
Pathological hypertrophy of cartilage cells (chondrocytes) is one of the key places in the development of osteoarthritis. These cells produce a large number of extracellular proteolytic enzymes – type 13 matrix metalloproteinase (MMP13) and aggrecanases, which contribute to the destruction and calcification of articular cartilage. The molecular mechanisms of regulation of chondrocyte hypertrophy have not yet been known.
A group of scientists from different scientific centers in the United States led by Fadia Kamal from the University of Pennsylvania decided to study the possible role of the enzyme G-protein-coupled receptor kinase 2 (GRK2) in this process. Earlier, the same researchers showed that the increased activity of this enzyme is associated with loss of receptor sensitivity and abnormal cell proliferation in heart and kidney diseases.
First, the authors of the work, using immunofluorescent staining, analyzed the activity of GRK2 in normal and ostearthritis-affected human cartilage and were convinced that it is increased by more than 400 percent during the disease (p <0.05) and continues to grow as it progresses. This finding was confirmed in a mouse model of osteoarthritis (surgical destabilization of the medial meniscus of the knee, DMM) and showed that increased GRK2 activity leads to desensitization of G-protein-coupled receptors in cartilage cells.
In two subsequent experiments, chondrocyte-specific knockout of the gene encoding GRK2 was either induced in mice after DMM, or they were injected with paroxetine. This antidepressant from the group of selective inhibitors of neuronal reuptake of serotonin, used since the 1990s, in addition to the main action suppresses GRK2 activity in vitro and in vivo… It was found that both effects restore the sensitivity of receptors coupled to the G-protein, slow down the progression of osteoarthritis and promote partial regeneration of cartilage tissue.
Moreover, only the administration of paroxetine, but not the disabling of the GRK2 gene, also suppressed the inflammation of the synovial membrane of the joint accompanying osteoarthritis. Experiments on the administration of another serotonin reuptake inhibitor to animals, fluoxetine, which does not act on GRK2, showed that this effect is associated with the serotonergic effects of paroxetine, independent of its chondroprotective effect.
Immunofluorescent staining of murine cartilage for markers of chondrocyte hypertrophy (ADAMTS5 and MMP13) and degradation of the extracellular matrix (neo-epitope of aggrecan) revealed that their production was significantly reduced by paroxetine (p <0.0001–0.05 for different markers). 3D reconstructions of the knee joints of animals using computed tomography showed that inhibition of GRK2 by this drug prevents joint mineralization, pathological bone remodeling under cartilage, and the formation of osteophytes (bone spines) after DMM (p <0.0001–0.05 for different parameters).
In conclusion, the researchers found that in cultured knee cartilage obtained during prosthetics in patients with osteoarthritis, paroxetine reduces the expression of GRK2, ADAMTS5 and MMP13, that is, it suppresses hypertrophy of cartilage cells and produces a direct chondroprotective effect.
The authors concluded that paroxetine may become the first disease-modifying drug for the treatment of osteoarthritis and filed
a patent application for this therapy.
–Chondroprotective effect of paroxetine in osteoarthritis
Fadia Kamal / Penn State
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This is not the first time that a fundamentally new clinically significant effect has been discovered in a known drug. A classic example is the well-known acetylsalicylic acid, which in low doses inhibits platelet aggregation, preventing thrombus formation. In addition, anti-inflammatory
diclofenac and combinations antidiabetic metformin with antihypertensive syrosingopine revealed anti-cancer properties, and an experimental drug for Alzheimer’s disease tideglusib it turned out
effective remedy against tooth decay.
Recently, staff members of the Universities of Washington in St. Louis and Duke in Durham offered a fundamentally new approach to the treatment of osteoarthritis. The bionic cartilage created by them on the basis of pork chondrocytes synthesized for itself the peptide anti-inflammatory drug anakinra in response to mechanical stress.
Oleg Lishchuk
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