LONDON – The control of bone resorption is closely linked to the function of the immune system, a new study has shown.

A team of researchers working in Germany has discovered that osteoclasts – the cells that constantly eat away at the bone, at the same time as other cells constantly produce new bone – are regulated by the immune system, using the same molecules that are present on antigen-presenting cells such as macrophages.

The study showed that, as a result, regulation of the immune system also has the capacity to stimulate the production of new bone or, conversely, to cause thinning of the bone.

Georg Schett, professor of internal medicine at the University of Erlangen-Nuremberg in Erlangen, Germany, told BioWorld Today, "What we have found is that bone is essentially controlled by the immune system. When you have a strong immune response, you lose bone. When the immune system is down-regulated, by contrast, you protect the bone."

The finding has immediate therapeutic relevance, he added. "We already have drugs in the clinic that can up-regulate or down-regulate the relevant immune response. The scientific finding that we now know how bone is regulated by the immune system is important, because diseases such as osteoporosis carry a huge economic and health burden. But the additional value of this study is that, rather than saying that we will, in five or 10 years' time, have new drugs to treat these conditions, it is the case that we do already have these drugs."

Schett said that the anti-inflammatory drug abatacept, for example, is already used to treat rheumatoid arthritis. "We already knew that abatacept was effective both for treating the inflammation of rheumatoid arthritis and for preventing the bone loss that occurs in this condition, but now we have an explanation for why it protects bone so well."

Schett and his collaborators reported their findings in the May 7, 2014, edition of Science Translational Medicine in a paper, titled "T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway."

The starting point for their study was the understanding that both osteoclasts and macrophages have the same molecules on their surfaces, which allow them to communicate with T cells. The scientists knew that the pair of molecules known as CD80/86, which are present on antigen-presenting cells (which include macrophages), are needed in order to interact with CD28 on the T cells. When that happens, the T cells become activated and an immune response is triggered.

Another molecule found on the surface of T cells, called CTLA-4, helps to regulate the activation process, because if activation continued unabated, the immune system would go into overdrive. CTLA-4 is able to block the interaction between CD80/86 on antigen-presenting cells and CD28 on T cells.

Schett's group therefore set out to investigate how the interactions affected the behavior of osteoclasts and the resulting effect on bone production.

They found that when they genetically modified mice so that the animals did not have copies of CD80/86 molecules on their macrophages and osteoclasts, the animals' bone density was lower than normal, because they had high numbers of osteoclasts.

Other experiments investigated what happened when they added CTLA-4 to osteoclasts in culture. With osteoclasts from wild-type mice, adding CTLA-4 normally prevents the cells from differentiating fully, thus impairing their ability to resorb bone. But when the researchers added CTLA-4 to the osteoclasts of mice that lacked CD80/86 molecules on their T cells, the cells continued to differentiate.

Other investigations, carried out on osteoclast precursor cells, showed that when CTLA-4 interacted with CD80/86, this had the effect of activating an enzyme called indoleamine 2,3-dioxygenase (IDO), and as a result the cells entered the pathway to apoptosis (programmed cell death).

In harmony with this finding, mice that had been genetically modified to lack IDO had high numbers of osteoclasts and osteoclast precursor cells and their bones were thinner than normal.

Schett observed that the blocking of the interaction between CD80/86 and CD28, by CTLA-4, is already used in an existing therapy to treat rheumatoid arthritis. The drug abatacept, which is a fusion protein of immunoglobulin G and CTLA-4, blocks the interaction with the aim of damping down the harmful immune responses that cause inflammation and damage to bone in rheumatoid arthritis.

"It's well known that this drug is very effective in blocking bone resorption in patients with rheumatoid arthritis," Schett said.

Conversely, another drug, called ipilimumab, is an antibody that targets CTLA-4 so that it can no longer interfere with the CD80/86 interaction with CD28, thus boosting the immune response. Ipilimumab is used in the treatment of malignant melanoma, to help the immune system seek out and destroy the tumor cells.

"Our study has immediate therapeutic implications for patients taking ipilimumab, because it suggests that they may be at increased risk of developing bone loss," Schett said.

Future studies by the team will aim to find out whether patients with malignant melanoma who are taking ipilimumab have a different bone composition than those who are not taking it.