Cannabinoid receptor 2 activation is key to preventing local and systemic inflammatory bone destruction in rheumatoid arthritis patients

The endocannabinoid system (ECS) is one of the most important systems in the human body. It is composed of cannabinoid receptor proteins (CB1 and CB2), chemical activators (endocannabinoids) and enzymes, and is widely distributed throughout the body, especially in the brain.

According to studies, the ECS influences all the major organ systems inside the body, including the immune system and the nervous system. As such, it is involved in a wide variety of processes, such as appetite, immunity, memory, metabolism, mood, pain, reproduction, sleep and stress.

The CB2 receptor is known as the peripheral receptor for cannabinoids. It is found mainly in immune tissues, which hints at a possible immune-modulating role. CB2 has been implicated not only as an important regulator of inflammation, but also of malignant bone destruction (osteolysis).

Hence in a recent study, researchers from The First Affiliated Hospital of Soochow University in China investigated the potential of a synthetic CB2 agonist in preventing osteolysis and inflammation associated with collagen-induced arthritis (CIA). An agonist is a chemical that binds to a receptor to induce a biological response. The researchers reported their findings in an article published in the Journal of Bone and Mineral Research.

The link between inflammation and bone loss in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of the synovium, the soft tissue that lines the entire inner surface of a joint. This inflammation mediates the bone loss that is typically seen in patients with RA.

The destruction of bones and cartilage in the later stages of RA is caused by bone cells called osteoclasts, which have white blood cell precursors. An increased production of pro-inflammatory molecules stimulates osteoclast activity, which leads to massive bone resorption — the process by which the body breaks down bones.

Active bone resorption without bone formation eventually leads to the weakening of bones (osteopenia), which is associated with a high risk of bone fracture. Because inflammation is the initiator of this detrimental cascade that leads to bone loss, current treatments for RA are focused on preventing systemic inflammation before it triggers the bone erosion process.

The role of CB2 receptor in regulating inflammation and bone loss

For their experiment, the researchers used a mouse model of CIA. They observed that CB2 expression in markedly higher in the synovium and bone tissue of CIA mice than in non-inflamed synovium and bone tissue.

When these samples were treated with JWH133, a synthetic CB2 selective agonist, the researchers reported that CIA was effectively suppressed. This was evidenced by the decrease in synovial enlargement (hyperplasia), inflammatory responses, cartilage damage and bone destruction. Treatment with the CB2 antagonist, SR144528, on the other hand, did not produce the same results.

The researchers also reported that JWH133 stopped osteoclast formation and bone resorption in CIA mice. In addition, it reduced the expression of key factors involved in osteoclast activation, such as RANKL, MMP-9, TRAP, CTSK and NFAT-1. This meant that mechanistically, JWH133 is capable of inhibiting RANKL-induced activation of osteoclast precursors.

Another thing that the researchers noted was that CB2 activation increased the expression of the anti-inflammatory protein interleukin (IL)-10, and reduced the expression of pro-inflammatory signaling molecules, such as TNF-a, IL-1B and IL-6. These activities clearly show the role of CB2 as a regulator of inflammation.

Based on these findings, the researchers concluded that CB2 agonists can be used to ameliorate RA-related bone destruction by inhibiting the generation of osteoclasts and modulating inflammatory responses. This mechanism of action highlights the potential of such compounds in the treatment of rheumatoid arthritis and the role of CB2 receptors in the prevention of bone loss.

Studies have been looking for more natural approaches for treating arthritis — visit ArthritisCures.news to learn more.

Sources include:

Science.news

NCBI.NLM.NIH.gov

UCLAHealth.org

Link.Springer.com

VeryWellHealth.com

ASBMR.OnlineLibrary.Wiley.com