Bone remodeling in the body involves a balancing act between osteoblasts, the cells that form bone, and osteoclasts, the cells that break it down. Diseases such as osteoporosis, arthritis and periodontitis involve bone loss and are related to excessive activity of osteoclasts.
In a new article published in the journal Proceedings of the National Academy of Sciencesresearchers of the University of Pennsylvania and colleagues offer new insights into osteoclast regulation, which could shed light on imbalances that can cause disease. The work identifies the IFT80 protein as a key player in the control of osteoclast populations. The team found that mice lacking IFT80 developed larger-than-expected osteoclast populations and subsequently developed severe osteopenia.
“When you think about translation to the clinic, we think this finding is very important,” he says. Shuying (Sheri) Yangassociate professor at Penn’s School of Dental Medicine and the lead author of the study. “As we begin to understand the mechanism and function of the IFT80 gene, we will be able to consider it as a potential therapeutic target. For example, a DNA- or mRNA-based therapy that introduces this protein could help treat certain bone diseases.”
Yang and colleagues became interested in IFT80 after a previous study in cell biology of nature. It revealed that IFTs, or intraflagellar proteins, play a role in T-cell protein transport. These proteins are a focus of Yang’s lab and the finding piqued his interest as T-cells and osteoclasts are derived from hematopoietic stem cells. , the precursors of blood cells. IFTs help build cilia, antenna-like sensory organs that extend from cells, by transporting proteins from the base of the cilia to their tip and back. In previous work, Yang et al. had shown that IFTs play a critical role in the regulation of osteoblasts and chondrocytes, cells that maintain cartilage, from mesenchymal stem cells, which produce and maintain bone, cartilage and other types of fabrics.
To explore the role of IFT80 specifically in osteoclasts, Yang’s group developed a line of knockout mice that lacked the protein in osteoclast precursors. Notably, they found that these animals had significantly lower bone volume compared to normal mice, and their osteoclasts nearly doubled in number. “It was a dramatic change,” says Yang.
The researchers found that IFT80 prevents osteoclast precursors from giving rise to bone resorbing cells and inhibits osteoclast maturation.
Further experimentation indicated that IFT80 interacted with a protein called Cbl-b in the protein degradation pathway regulated by the small regulatory protein ubiquitin in osteoclasts. Yang’s team found that IFT80 prevents the breakdown of Cbl-b, and Cbl-b normally degrades another protein called TRAF6. TRAF6 normally promotes osteoclast production, so by degrading TRAF6, IFT80 inhibits osteoclast differentiation.
Downstream of TRAF6, the research team also found evidence that IFT80 suppresses a signaling pathway governed by the RANKL and RANK proteins.
To test the idea that IFT80 is a potential target for intervention in bone loss disorders, the researchers overexpressed IFT80 in a mouse model that normally experiences bone loss caused by hyperactive osteoclasts. By doing so, it effectively reduced RANK/RANKL activation, reduced osteoclast production, and increased bone volume in the mice.
The study is the first to link IFT80 to a role in osteoclasts and to find that IFT80 controls a protein degradation pathway and acts as a negative regulator during osteoclast differentiation. These characteristics make it a valuable target for potential therapeutic intervention, says Yang.
“Right now there is a lot of interest in how the body promotes osteoclast differentiation,” she says. “With so many diseases linked to excessive bone loss—osteoporosis, periodontitis, rheumatoid arthritis, and even fractures—there is a great need to find ways to address bone loss and restore balance to bone remodeling.”
Shuying (Sheri) Yang is an Associate Professor in the Department of Basic and Translational Sciences at the University of Pennsylvania School of Dental Medicine.
Yang co-authored the study with Vishwa Deepak, Shu-ting Yang, Ziqing Li and Xinhua Li of Penn Dental Medicine; Andrew Ng and Ding Xu of the State University of New York at Buffalo; Yi-Ping Li of Tulane University; and Merry Jo Oursler of the Mayo Clinic School of Medicine.
The study was supported by the National Institutes of Health (grants DE023105, AR066101, and AG048388).