Yale researchers identify gene as target for osteoporosis treatment

Back to news list


Like every other organ in the body, bone is in constant flux. Cells called osteoblasts lay down new bone, competing with osteoclasts, which tear up old bone. If you’re past your mid-20s, your osteoblasts are already fighting a losing battle. They can’t keep up with the bone-destroying osteoclasts, and if you haven’t built up enough of a reserve in the first few decades of your life, you’ll end up with osteoporosis in the last few—a disease which leaves bones weakened and brittle. In extreme cases, a cough or a sneeze can snap a bone.

Researchers at the Yale School of Medicine, Imperial College London, and Boehringer Ingelheim Pharmaceuticals have identified a new therapeutic target to inhibit the bone loss characteristic of osteoporosis. Their findings were published on August 14 in Cell Report. The team, led by Agnès M. C. Vignery, .D.DS., Ph.D., senior research scientist in orthopaedics and rehabilitation, and cell biology, discovered that a gene called Kcnn4 was involved in the formation of osteoclasts, which form when multiple macrophages fuse together. Blocking that gene, and thus osteoclast formation, could tip the scales in favor of osteoblasts.

“Many inhibitors of Kcnn4 have been well characterized,” says Benjamin Podbilewicz, Ph.D., a professor of biology at Technion-Israel Institute of Technology, who was not involved in the study. “It is exciting that existing and new drugs specific to Kcnn4 may be used to treat chronic inflammation and bone resorption diseases where macrophage-macrophage merger play important functions.”

Like any other organ, bone has to be renewed. “It’s a very tightly controlled event because you don’t want to lose too much or make too much,” said Vignery. While skin cells can slough off into space, osteoclasts have to remove old and non-functional bone tissue so that osteoblasts can replace it with new material.

But researchers can’t block osteoclast activity without also affecting the immune system, because macrophages, the building blocks of osteoclasts, are first and foremost immune cells. Any drug that affects macrophages in general will also affect immune function. To get around that functional overlap, Vignery’s lab has been looking for molecules that are highly expressed, or expressed exclusively, at the onset of macrophage fusion—when the cells form osteoclasts and lose their immune function.

The UK group tracked single nucleotide polymorphisms in mRNA expression levels throughout the genome to identify a network of genes they thought might be involved in the regulation of macrophage multinucleation in rats. Using a microarray analysis and quantitative reverse transcription PCR, they identified one gene within that ‘Macrophage Multinucleation Network’—Kcnn4—whose expression peaked during macrophage fusion. Kcnn4 codes for a potassium channel activated by calcium inside of cells.

To confirm that Kcnn4 really played a role in osteoclast formation, they inhibited its function with pharmacological blockers and targeted gene deletion and RNAi in osteoclasts of both rats and humans. They found that blocking Kcnn4 function decreased macrophage fusion in both rodent and human cells. Further, in mouse models, mice without a functional Kcnn4 gene had fewer osteoclasts and greater bone mass and density—by as much as 30 percent in some cases.

“While cell-to-cell fusion is very important in both normal physiology and in different diseases, our understanding of the mechanisms that control fusion stages is still very limited,” says Leonid Chernomordik, Ph.D., a senior investigator in the section on membrane biology at the NIH who was not involved in the study. “This work is a major breakthrough in research on macrophage fusion.”

A Kcnn4 targeted therapy could replace current bisphosphonate-based treatments for osteoporosis. Bisphosphonates latch onto calcium and become integrated into the bone. When osteoclasts encounter the bisphosphonates, they ingest the drugs, which cause the cells to undergo apoptosis. But halting bone turnover completely by killing osteoclasts can actually weaken the bone and cause unusual (and thus, hard to treat) fractures. Since the drugs accumulate in the bone their effects are not easily reversed.

Kcnn4 appears to be a promising, reversible target to block the formation of osteoclasts. However, Kcnn4 has multiple functions. It is also associated with many other diseases in humans including autoimmune encephalomyelitis, neurodegeneration, and Crohn disease. “Based on the multiple functions of Kcnn4, this channel may have secondary effects and may not be a magic bullet to treat bone resorption and chronic inflammation,” says Podbilewicz. But thanks to the high expression of Kcnn4 in osteoclasts, it might still be possible to develop drugs that specifically target macrophage fusion, according to Vignery.

While Kcnn4 clearly has a role in macrophage fusion, the precise mechanism by which it controls the process remains unknown. “We still do not know what are the proteins that directly fuse macrophages to form giant multinucleated cells (osteoclasts) in bones and during inflammation,” says Podbilewicz. “Maybe some genes in the genetic network uncovered by [this study] could be the fusion proteins that researchers have been extensively looking for over many decades.”


This Article was submitted by Claire M. Bessinger - Van Graan, on Thursday, August 14, 2014.