How do bones and the immune system communicate? The answer to this question is beginning to be answered thanks to a relatively new area of study called osteoimmunology. Over the past decade, work in the field has revealed that inflammation and immune activation can lead to bone damage. This crosstalk between the signal-transduction pathways of the immune and skeletal systems occurs at both the cellular and molecular levels and plays a key role in the pathogenesis of rheumatoid arthritis.
Rheumatoid arthritis is a chronic autoimmune disease that causes inflammation of the joints and affects about 1 percent of the U.S. population. It occurs when the immune system mistakenly attacks the healthy joint tissue for reasons that are not yet fully clear. While many of the currently available antiarthritic drugs are effective at suppressing inflammation associated with the disease, they offer poor or no protection against bone damage. Therefore, a therapeutic agent that attenuates both symptoms is being pursued.
In the paper entitled “Celastrus and its bioactive celastrol protect against bone damage in autoimmune arthritis by modulating osteoimmune cross-talk,” investigators at the University of Maryland, Baltimore, sought to do just that. The group studied the antiarthritic effects of Celastrus aculeatus Merrill (celastrus) and its bioactive component celastrol in the adjuvant-induced rat model of rheumatoid arthritis. The roots, stem and leaves of the plant have been used for centuries in traditional Chinese herbal medicine to treat various inflammatory diseases. However, the mechanisms underlying the antiarthritic activity of celastrus have not been fully examined.
The study, published in the Journal of Biological Chemistry, begins by looking at the effect of celastrus/celastrol on the joints of arthritic rats. The joint is lined by a layer of cells called the synovium. At the cellular level, mediators of the immune system known as leukocytes, commonly referred to as white blood cells, infiltrate the synovium and cause inflammation. As the disease progresses, the inflamed synovium invades and destroys the cartilage and bone within the joint. This process is referred to as synovial mononuclear cell infiltration and pannus formation and is is a key parameter studied in this paper.
According to Kamal Moudgil, the lead researcher on the study, “Most investigators are studying the lymph nodes that drain the joints or the spleen, because everything goes through the blood. But then we realized that, until we study the immune system or the cells in the joints, maybe we would never get the right picture … because peripherally we are only trying to make a speculation there [in the lymph nodes] and extend it to the joints.”
Upon histological examination of the joints in the hind paws of arthritic rats fed celastrus or injected intraperitoneally with celastrol, it was shown that there was a significant reduction in synovial mononuclear cell filtration and bone and cartilage destruction. Furthermore, bone loss and the number of osteoclasts, the cells required for bone resorption (breakdown), were reduced (see figure). These results indicated that celastrus/celastrol is effective in suppressing inflammation as well as bone damage in joints of arthritic rats.
The mechanisms underlying the observed antiresorptive effect also were elucidated by determining the effects of these natural products on several key immune mediators of inflammation-induced bone damage. There was a significant decrease in GM-CSF, M-CSF, OPN and IGF-1 produced by the synovial infiltrating cells of celastrus/celastrol-treated rats and a consequent inhibition of osteoclastic activity in their joints. More importantly, there was a decrease in receptor activator of nuclear factor-β ligand, or RANKL, the dominant mediator of the osteoclastic bone remodeling via the RANKL/RANK/OPG pathway.
The production of the aforementioned immune mediators was stimulated by proinflammatory cytokines further upstream in the osteoclastogenic signaling pathway such as IL-17, IL-6, IL-1β and IL-18. Matrix metalloproteinase, or MMP, an enzyme that plays an important role in cartilage and bone destruction in arthritic joints, was shown to be an effector molecule downstream of RANKL in the pathway.
In summary, the results indicate that the herb celastrus and its bioactive component celastrol reduced inflammation and bone destruction in the joints via several different mechanisms:
1) reduction of key mediators of osteoclastogenesis,
2) suppression of the key upstream inducers of osteoclastogenesis and
3) suppression of downstream effectors of the osteoclastogenic mediators.
While it is unclear whether any of these mechanisms is more dominant than another, Moudgil says, “We believe that it is a coordinated cascade. Physiologically, I think all three steps are critical and may be playing an additive role.”
Up until now, celastrus/celastrol had been credited mostly for its antitumor activity. This paper is the first to demonstrate the protective effect of celastrus/celastrol on bone damage in vivo in arthritic animals. As such, the compounds may be promising antiarthritic agents for the concurrent treatment of inflammation and bone damage associated with arthritis and “should be further tested in rheumatoid arthritis patients for their utility as adjuncts to conventional drugs,” Moudgil says.
Shannadora Hollis (firstname.lastname@example.org) received her B.S. in chemical engineering from North Carolina State University and is a Ph.D. student in the molecular medicine program at the University of Maryland, Baltimore. Her research focuses on the molecular mechanisms that control salt balance and blood pressure in health and disease. She is a native of Washington, D.C., and in her spare time enjoys cooking, thrift-store shopping and painting.