A novel gene could become a key player in the treatment of bone loss, one of the fastest growing problems for rheumatologists. Schnurri-3 and small molecule inhibitors of the gene’s proteins could emerge as new agents to increase bone mass.
“Osteoporosis is one of the most common diseases in the world, if not the most common,” said Laurie Glimcher, MD, the Stephen and Suzanne Weiss Dean at Weill Cornell Medical College. “Schnurri-3 seems to have its effect primarily in bone formation. The pot of gold at the end of the research rainbow is finding small molecules that target the bone-forming cell, the osteoblast, to promote good bone formation in the osteoblast that will complement the drugs currently available that inhibit bone resorption.”
Dr. Glimcher will present current research into Schnurri-3 and hopes for future therapeutic agents during the 2015 Rheumatology Research Foundation Oscar S. Gluck, MD, Memorial Lecture: Close to the Bone: Schnurri-3 – A Novel Gene that Remodels the Skeleton from 1:00 – 2:00 pm Monday.
Rheumatologists are seeing growing numbers of patients with bone loss, she said. In the general population, the prevalence of chronic bone loss is growing as the population ages. Bone loss is a side effect of both rheumatologic disease and many of the common treatments.
Osteoporosis is the disease of primary concern. There is a significant need for agents that increase bone formation in inflammatory arthritis and in cancer.
Rheumatoid arthritis and other inflammatory arthropathies often produce painful bony erosions in the joints. Existing drugs can halt further bone loss, but no agents currently exist that help stimulate bone formation to replace bone and heal the erosions.
“Inflammation leads to the activation of osteoclasts, which then resorb bone in the joint, leading to erosions,” Dr. Glimcher said. “We can reduce inflammation with TNF blockade or by calming the immune system on the T cell side. Those kinds of treatments can slow bone loss, but how do you regrow bone that is already lost? We need to increase bone formation to repair those erosions.”
Certain types of cancer, including breast, lung, and myeloma, often metastasize to bone, she said. The resulting bony lesions are extraordinarily painful for patients. For now, there is no effective treatment. But there is Schnurri-3.
Dr. Glimcher and co-workers discovered a new protein and its associated gene that is a potent regulator of bone formation by osteoblasts. Inhibition of the gene, Schnurri-3, and its associated protein result in the accelerated formation of bone mass.
Schnurri proteins play key roles in the regulation of bone mass by down regulating the activity of extracellular signal-regulated kinase. This down regulation reduces osteoblast differentiation. Inhibiting the down regulation acts to increase osteoblast differentiation and results in the production of more osteoblasts and increased bone formation.
“Schnurri-3 is a great target because if you block it, at least in mice and in cultured human osteoblast progenitor cells, the only effect we have been able to find is increased bone mass,” Dr. Glimcher said. “We have looked extensively for changes in other organs and in important biological processes and did not find any alterations. The effects of inhibiting Schnurri-3 seem to be limited to bone. Not only do you get increased bone, you get good bone, mechanically and biophysically strong with good lamellar structure.”
Schnurri-3 inhibition is promising, but clinicians should not expect any new therapeutic agents based on the gene soon. Dr. Glimcher’s lab is working with private sector partners to develop small molecule inhibitors, but clinical work has barely begun.
“We desperately need new therapies that build bone,” she said. “We are looking at the effect of blocking Schnurri-3 in the setting of mouse models of rheumatoid arthritis, osteoporosis, and the painful lesions that are associated with bony metastases in breast cancer. We know more about the mechanisms by which Schnurri-3 works, but much work remains to be done.”