Amgen’s sclerostin research ties in well with the latest thinking about bone biology at the cellular level.
The skeleton, while strong, isn’t made of static tissue. It undergoes continuous change as cells called osteoclasts degrade bone and osteoblasts make new bone. The skeleton’s primary function is to provide structural support for the body, and it has been known for a long time that during adulthood the exact shape of bones, and the total amount of bone in the body, changes dynamically. This ongoing skeletal adaptation is greatly influenced by the amount of mechanical strain that the skeleton senses as a result of everyday movement and physical activity.
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How does the skeleton “feel” mechanical strain? How does it turn this information into the act of making more or less bone? This has been a central question in bone biology for many years.
There’s another bone cell, called the osteocyte, that acts differently from other types of bone cells. Osteocytes aren’t located on the surface of bone, instead they’re found embedded within bone. Osteocytes look strange, too.
“This funny, starfish-like cell is the most abundant cell in bone,” says Amgen’s Chris Paszty, scientific director, Metabolic Disorders.
The osteocyte’s projections enable it to reach out to other osteocytes in the bone as well as to osteoblasts and bone lining cells on the bone surface, forming a huge interconnected mesh reminiscent of nerve cell networks.
The Osteocyte and the Mystery Signal
For many decades after their discovery, the function of osteocytes was unknown. In the mid-1980s bone biologists started generating data that supported the general hypothesis that the nerve-like osteocyte network embedded throughout bone might be a mechanosensor that allowed the skeleton to “feel” and respond to mechanical strain.
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Amgen Research: Investigating Targets Involved in Building Bone With more than 75 million people worldwide suffering from osteoporosis, and others who experience bone loss from inflammatory diseases and procedures such as radiation treatment, there’s a serious patient need for therapeutics that help halt bone erosion and build bones. The sclerostin antibody, which Amgen is developing in collaboration with UCB, targets osteoblasts, and it is being investigated for its potential to increase bone mass in humans. But, if sclerostin represents the brake for bone growth, how could this knowledge be applied to a therapeutic approach to help build bone? “There are brakes on many biological processes in your body,” explains Chris Paszty, Amgen scientific director, Metabolic Disorders. “The sclerostin brake is important for not making too much bone – in a healthy body, the brake provides balance.” Amgen’s research team went after – and generated – a clinical candidate antibody that blocks sclerostin and is being evaluated for its potential in various conditions and diseases associated with bone loss to, essentially, take the foot off the brake to help the body build more bone. |
Years of work by bone biologists culminated in the prediction of the existence of a powerful and cryptic inhibitory signal produced by the osteocyte network that would likely represent a master regulator of the skeleton. No one at the time had any idea what the nature or identity of that signal might be. That is, until genetic mapping and gene expression data generated by Celltech (which has since been acquired by UCB), and preclinical data generated by Amgen’s research team, pointed toward a protein in the body called “sclerostin.”
“Sclerostin is specifically made by osteocytes – it is a secreted protein so it can travel and pass information on to other cell types and it acts as a natural brake on bone formation, preventing the body from making too much bone,” explains Paszty. “Sclerostin is a master regulatory molecule produced by the master regulatory network in bone. So, the thought is that in a healthy body, if you need more bone, the osteocytes make less sclerostin. If there’s a need to inhibit bone formation, the osteocytes make more sclerostin.”
“It was thrilling to see this all come together so nicely, with sclerostin meeting the criteria of being that mysterious and potent inhibitory signal that bone biologists had predicted was produced by osteocytes,” Paszty says, “and so in terms of treating certain diseases, if you need to rebuild bone, then a molecule, such as an antibody, that could block sclerostin might do the job.”
Amgen’s research team developed a key approach for identifying antibodies that target blocking sclerostin. They have presented data at scientific conferences over the past several years on the effects these antibodies have on increasing bone formation, bone mass and bone strength in preclinical models.
Amgen is currently developing, in collaboration with UCB, a candidate antibody that targets sclerostin for potential therapeutic use in various conditions and diseases associated with bone loss.
One key aspect of Amgen and UCB’s sclerostin research, Paszty notes, is that “by blocking sclerostin, we are specifically targeting one of the fundamental ways by which the body normally controls bone formation and bone mass.”
Phase I trials in healthy postmenopausal women and in healthy men have been completed for the sclerostin antibody. Initial data from this study were released at the 2007 annual meeting of the American Society for Bone and Mineral Research.
