New Remedy Goal May Counter Bone Loss

Overactive populations of osteoclasts would possibly lead to a number of issues equivalent to osteoporosis, arthritis, and most cancers.

A brand new serve as for a protein that regulates osteoclasts—the cells that smash down bone—has been found out through researchers, and it’s going to pave the best way for the introduction of recent remedies to stop bone loss.

Bone reworking within the frame is a gentle balancing act between osteoblasts, cells who produce bone, and osteoclasts, cells who smash it down. Sicknesses like osteoporosis, arthritis, and periodontitis all purpose bone loss and are related to an building up in osteoclast process.

Researchers from the College of Pennsylvania and associates be offering new perception at the law of osteoclasts in a up to date find out about that was once printed within the magazine Court cases of the Nationwide Academy of Sciences, probably losing mild at the imbalances that can result in illness. The find out about recognized the protein IFT80 as a the most important part in controlling osteoclast populations. The researchers additionally found out that mice lacking IFT80 had larger-than-expected populations of osteoclasts and advanced critical osteopenia.

“While you consider translation to the hospital, we imagine this discovering is essential,” says Shuying (Sheri) Yang, an affiliate professor in Penn’s College of Dental Medication and the find out about’s senior creator. “As we start to perceive the mechanism and the gene serve as of IFT80, we might be able to imagine it as a possible healing goal. For instance, a DNA– or mRNA-based therapy that introduced this protein could help treat certain bone diseases.”

After seeing an earlier study in Nature Cell Biology, Yang and colleagues became interested in IFT80. That study discovered that IFT, or intraflagellar proteins, are involved in T cell protein transport. Yang’s lab studies these proteins and the finding caught her attention since T cells and osteoclasts are both produced from hematopoietic stem cells, the precursors of blood cells.

IFTs aid in the formation of cilia, which are antenna-like sensory organs that extend from cells, by transporting proteins from the cilia’s base to its tip and back again. Yang and colleagues previously demonstrated that IFTs serve key roles in regulating osteoblasts and chondrocytes, cells that maintain cartilage, from mesenchymal stem cells, which produce and maintain bone, cartilage, and other tissue types.

To explore the role of IFT80 specifically in osteoclasts, Yang’s group developed a knockout mouse line that lacked the protein in precursors of osteoclasts. Notably, they found these animals had significantly lower bone volume compared to normal mice, and their osteoclasts nearly doubled in number. “It was a dramatic change,” Yang says.

The researchers found that IFT80 prevents osteoclast precursors from giving rise to the 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 proteins RANKL and RANK.

To test the idea of IFT80 being a potential target for intervention in bone loss disorders, the researchers overexpressed IFT80 in a mouse model that normally experiences overactive osteoclasts-caused bone loss. Doing so effectively tamped down RANK/RANKL activation, lowered osteoclast production, and increased bone volume in the mice.

The study is the first to link IFT80 with a role in osteoclasts and to find that IFT80 controls a protein degradation pathway and serves as a negative regulator during osteoclast differentiation. These features makes 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 related to excess bone loss—osteoporosis, periodontitis, rheumatoid arthritis, even fractures—there is a big need to find ways to address bone loss and restore balance in bone remodeling.”

References:

“IFT80 negatively regulates osteoclast differentiation via association with Cbl-b to disrupt TRAF6 stabilization and activation” by Vishwa Deepak, Shu-ting Yang, Ziqing Li, Xinhua Li, Andrew Ng, Ding Xu, Yi-Ping Li, Merry Jo Oursler and Shuying Yang, 21 June 2022, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2201490119

“Intraflagellar transport is required for polarized recycling of the TCR/CD3 complex to the immune synapse” by Francesca Finetti, Silvia Rossi Paccani, Maria Giovanna Riparbelli, Emiliana Giacomello, Giuseppe Perinetti, Gregory J. Pazour, Joel L. Rosenbaum, and Cosima T. Baldari, 25 October 2009, Nature Cell Biology.
DOI: 10.1038/ncb1977

The study was funded by the National Institutes of Health.