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New Avenue Identified for Attacking Diseases of the Bone

microRNA-based therapeutics may one day help treat bone loss seen in diseases such as osteoporosis and rheumatoid arthritis, according to new research published this week in Nature Communications. The study is the first to identify microRNA-182 as a key regulator of bone health, to provide proof of concept that microRNA-182 inhibitors may be useful to treat certain diseases of the bone, and to show that microRNA-182 may be useful as a biomarker to monitor inflammatory bone diseases.

"Our study is the first exploration of key RNAs that would be used to develop a microRNA-based therapeutic strategy to treat bone diseases," said principal study investigator Baohong Zhao, PhD, assistant scientist in the Arthritis and Tissue Degeneration Program at Hospital for Special Surgery (HSS), and assistant professor at Weill Cornell Medical College, both in New York City. "Inhibition of microRNA-182 could have very promising therapeutic implications in the future disease treatment of inflammatory bone diseases, such as rheumatoid arthritis."

Bone destruction is a major characteristic and severe consequence of multiple skeletal diseases, including osteoporosis and inflammatory arthritis. These diseases have a significant impact on patient quality of life and increase the risk of disability.

MicroRNAs play key roles in a variety of biological and pathological processes and have recently gained increasing clinical attention as promising therapeutic targets or biomarkers. Recent studies support the use of microRNAs for the treatment of cancer, metabolic disorders, and infectious diseases such as hepatitis C virus, but little is known about microRNA’s therapeutic role in bone health.

"Skeletal diseases, such as postmenopausal osteoporosis and inflammatory arthritis, such as rheumatoid arthritis, are very common," said Dr. Zhao. "We set out to identify novel therapeutic targets to treat these refractory diseases. microRNA-182 came out as the top candidate for playing a role in inflammatory bone diseases, in a genome-wide screening of microRNAs."

A genome-wide screening of microRNAs identified microRNA-182 as a regulator of inflammatory osteoclast differentiation. The health of the human skeleton depends on a delicate equilibrium between bone resorption by osteoclasts and bone formation by osteoblasts. Bone destruction in rheumatoid arthritis and postmenopausal osteoporosis is mainly attributable to the abnormal activation of osteoclasts.

In basic science experiments, the researchers demonstrated that deletion of microRNA-182 protects against excessive osteoclastogenesis and bone resorption in models of ovariectomy-induced osteoporosis and inflammatory arthritis. Pharmacological treatment of these diseases with microRNA-182 inhibitors completely suppressed pathologic bone erosion.

In other experiments, the researchers discovered that the level of microRNA-182 expression in humans is strongly correlated with rheumatoid arthritis. "The data reveal a strongly positive correlation of microRNA-182 expression with rheumatoid arthritis pathogenesis and bone resorption," said Dr. Zhao. "In patients with rheumatoid arthritis, we can see much higher levels of this microRNA-182 than in healthy donors."

The researchers also evaluated microRNA-182 levels in 10 patients with rheumatoid arthritis and found anti-inflammation treatment controlled the disease and significantly decreased microRNA-182 levels, returning them to healthy donor levels. "Our promising data indicate that inhibition of microRNA-182 could not only have therapeutic implications," said Dr. Zhao. "microRNA-182 could be also used as a biomarker to track disease progress and potentially the benefits of treatments."

This research was supported by the National Institutes of Health.