In new work, HSDM researchers have identified a molecular pathway key to the early-stage degenerative process that underlies osteoarthritis. The discovery could guide the development of drugs to delay this bone-and-joint disorder, which afflicts more than 30 percent of Americans over age 65.
Though pain, stiffness and other symptoms may not appear until a person enters her 60s or 70s, joint damage silently begins about 20 years earlier. Until now, however, few scientists have had molecular and genetic tools to investigate the disease at its earliest stages, when intervention would make the greatest impact. Most work has, instead, focused on treating late-stage osteoarthritis to relieve patients’ pain and increase their mobility.
“We are the first group to look at the whole process,” said senior author Yefu Li, HSDM assistant professor of developmental biology. “The advantage we have is our mouse models.”
Li’s lab outfitted four strains of mice with alterations that cause the animals to develop humanlike osteoarthritis. In two of these strains, the surgical changes mimic sports injuries; in the rest, genetic changes cause osteoarthritis to emerge unusually early in life. In all four strains, the same early-stage cascade of molecular signals led to joint degeneration, while normal mice did not show these signals and did not develop the disorder.
This work began in 2005, when Li first observed that too much of one protein, called DDR2, went hand in hand with too much of another, MMP-13, already known to degrade cartilage cells, or chondrocytes. In 2009, Li showed that reducing gene expression of DDR2 by half could dramatically postpone osteoarthritis in mice genetically programmed to get the disease early in life. Instead of joint degeneration taking six months to emerge, the disease now took a year.
Li’s latest work, published in Histology and Histopathology in May, expands upon the osteoarthritis cascade. Joint problems begin, Li has found, with mechanical stress from overuse. At some critical point still unknown, cartilage cells respond by activating an enzyme called HtrA1.
Normally, joint chondrocytes float in a mesh of fibrous collagen protein. They never touch the collagen, thanks to a protective coating of matrix molecules. When chondrocytes turn on HtrA1 production, however, the process uses up many of these matrix molecules. Chondrocytes, now stripped of their protective coating, bump into the collagen mesh. It is this contact that stimulates the production of DDR2, which in turn generates the damaging MMP-13 enzyme.
In a quest to prevent these debilitating events, Li has already begun working with industry collaborators to develop a DDR2 inhibitor. The discovery of a second possible drug target in HtrA1 could boost the chances of developing an osteoarthritis-preventing drug, Li said.
Optimism buoys the lab. “I think osteoarthritis could be prevented in ten years,” said Li, who continues to investigate the genetic underpinnings of joint deterioration, step by step.
For more information, students may contact Yefu Li at yefu_li@hms.harvard.edu.
Conflict Disclosure: The authors declare no conflict of interest.
Funding Sources: The National Institutes of Health; the authors are solely responsible for the content of this work.
