Researchers at King's College London have discovered that an immune protein best known for protecting the body against infection also plays an important role in maintaining healthy bones.
The research published in PNAS, reveals that the protein collectin-11 supports normal bone remodelling by enabling the formation and function of osteoclasts - specialised cells responsible for breaking down old or damaged bone so that new bone can form.
Collectin-11 has an important role in the immune response. It acts as a first responder against infection by recognising sugar patterns on bacteria and viruses and then triggering a sequence of other proteins that activate the immune response. Until now, its function outside of immune defence had not been fully understood. The researchers found that collectin-11 produced in the bone marrow plays a critical role in ensuring a healthy supply of osteoclasts.
Using mouse models, the researchers demonstrated that when collectin-11 is absent along with one other protein in the sequence that it activates as part of the immune response, osteoclast formation is impaired. As a result, normal bone remodelling fails, leading to the accumulation of age-related bone damage and reduced bone strength in mice.
In the lab, when collectin-11 was added back to stem cells derived from the bone marrow of mice lacking these proteins, the stem cells were able to generate osteoclasts. The researchers found this mechanism operated in the same way in human cells. Human stem cells lacking collectin-11 were unable to generate osteoclasts unless the missing protein was restored.
These findings could help to explain the biology behind skeletal abnormalities observed in children born with rare genetic mutations affecting collectin-11, including cleft palate and abnormal development of bones in the skull (known as 3MC syndrome).
At a molecular level, the research showed that osteoclasts depend on collectin-11 to communicate with part of the immune system that operates locally in bone. Targeting this communication could represent a potential new therapeutic avenue for conditions in which abnormal osteoclast activity contributes to bone pathology. These include osteoporosis, erosive osteoarthritis, and bone disease associated with metastatic cancers such as breast, prostate, and lung cancer.
Steven Sacks, Professor of Nephrology at King's College London and senior author of the paper, said: "Our findings highlight an unexpected link between the immune system and bone health and identify a potential new target for treating osteoporosis and cancer-related bone disease, where excessive osteoclast activity can damage bone. The research also shows how immune proteins can play an unexpected but important role in maintaining long-term health."
"As a kidney specialist working in immunity and transplantation, I was surprised that this research led to a discovery about bone. It highlights the value of maintaining a broad perspective and working in a supportive cross-disciplinary environment."
Professor Steven Sacks, Professor of Nephrology at King's and senior author of the paper
Dr Mark Howard, former Research Associate at King's College London and first author of the paper, said: "It is an enjoyable coincidence that my earlier work in bone development should intersect with our current research in immunity. That a bone health mechanism would emerge from this convergence of knowledge is particularly satisfying. Even more exciting is the potential link to metabolic bone disease, which may open the door to entirely new therapeutic approaches."
Current treatments that suppress osteoclast formation can be effective but may have significant side effects. The researchers are now working to develop drugs that block collectin-11 interactions in specific disease contexts. These treatments could provide an alternative or complementary approach, offering more targeted control of osteoclast activity.
The research was supported by the Medical Research Council.
Read the full paper in PNAS.
