Bone is continually recycled to maintain its strength through competition action of osteoclasts, cells that break down aging bone, and osteoblasts, which form new bone. Osteoclasts also play a role in common diseases that erode the bone, where two signaling molecules, TNF and RANKL, cause bone loss too. Both are known to activate the complex of nuclear factor kappa B (NF-kB), which turns on genes that cause the stem cell precursors to mature osteoclasts and start eating the bones. Meanwhile TNFa and RANKL to promote bone loss, the study argues that TNFa and RANKL have different effects on the levels of a key inhibitory protein within the NF-kappaB pathway called NF-kB P100, with important implications for the design of drugs.

The NF-kappaB as a route signals around for more active osteoclasts, but NF-kB P100 (P100) interferes with the ability of that path to transmit the signal of bone loss. Meanwhile TNFa and RANKL activate NF-kB signaling, RANKL p100 efficiently converts into a form that is no longer blocking NF-kappaB signaling pathway and leads to bone loss. In contrast, the current study is the first to show that TNFa P100 can build. Thus, TNFa, both causes bone loss through NF-kB signaling and limits through the accumulation of p100.

The experiments also found that mice genetically engineered to lack NF-κB2 P100 suffered erosion of more severe joint inflammation and their normal littermates in the face of TNFa. TNFa, but not RANKL, also increased levels of a protein in osteoclast precursors, called TNF receptor-associated factor 3 (TRAF 3), which can help block NF-kB P100 osteoclast formation and inflammation .

“As more studies are required to confirm and detail of this mechanism, the results underline that the increasing levels of either TRAF3 or NF-kB P100 could represent a powerful new way to limit bone destruction and inflammation induced bone loss seen in osteoporosis and rheumatoid arthritis, “said Brendan Boyce, MD, professor in the Department of Pathology and Laboratory Medicine at the University of Rochester Medical Center and the study’s corresponding author. “NF-kB P100 levels may vary with each person’s genes, making some more sensitive to TNFa-driven disease. Future solutions may be local delivery of p100 in diseased joints through gene therapy, or a drug target enzyme, NIK, which otherwise limits the supply p100.

At the Center of bone loss and inflammation

Drugs that block TNF function are blockbusters (eg, Enbrel, Humira and Remicade), because effectively prevent bone loss and inflammation in most patients with rheumatoid arthritis. They have also been shown to reduce bone loss in women soon after menopause.

Other studies, however, have suggested that TNF may not make stem cells to be less than osteoclasts RANKL first “prime” them. “The debate has been lively, and it goes to the molecule a target near future attempts to design more precise drugs.

The current results show that TNFa may indicate bone loss without RANKL, NF-kB providing P100 is also absent. In mice with RANKL or engineering or NF-kB P100, Boyce and his colleagues found that TNF had significantly increased the ability of the signal for the maturation of osteoclasts and bone loss in this scenario.

Another unexpected result was measured in changes in gene expression, the process by which information encoded in DNA strands used to build proteins that form the structures of the body and carry messages. The team found that mice engineered to over-express TNF, but also to lack NF-kB P100, has significantly increased inflammation in the joints, compared with mice with elevated levels of TNFa, but also present to counteract p100 .

Along with Boyce, the study was led by Xing Lianping Zhenqiang Yao and the Department of Pathology and Laboratory Medicine at the University of Rochester Medical Center. The study was funded in part by the National Institutes of Health.

“We believe that NF-kB P100 limits of maturation of osteoclasts, not only, but also the number of inflammatory cells attracted to the joints in response to TNF,” said Boyce. “If confirmed, would mean that P100 is more than one role in more than a big bone disease, so it would create new opportunities to reverse the disease by manipulating the levels of p100.