Scientists at UT Southwestern report that mice with higher than normal levels of miR-34a had increased bone mass and reduced bone breakdown. This outcome is achieved because miR-34a blocks the development of osteoclasts, which make the bone less dense and prone to fracture, according to the researchers.
miR-34a is a type of microRNA (miRNA) that serves as a brake to help regulate how much of a protein is made, which in turn determines how cells respond.
“This new finding may lead to the development of miR-34a mimics as a new and better treatment for osteoporosis and cancers that metastasize to the bone,” said senior author Yihong Wan, Ph.D., assistant professor of pharmacology and member of the UT Southwestern Harold C. Simmons Cancer Center.
Her team found that injecting nanoparticles containing an artificial version, or mimic, of miR-34a into a mouse with post-menopausal osteoporosis decreased bone loss. “Interestingly, the mouse miR-34a is identical to that in humans, which means that our findings may apply to humans as well,” added Dr. Wan, who is also a Virginia Murchison Linthicum Scholar in Medical Research at UT Southwestern.
The study (“miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2”) is published in Nature.
High levels of bone destruction and reduced bone density caused by excessive osteoclasts are characteristic of osteoporosis, a common bone disease in which bones become fragile and susceptible to fracture. This condition disproportionately affects seniors and women, and leads to more than 1.5 million fractures annually.
miR-34a could have an additional therapeutic application, offering protection from bone metastases in a variety of cancers, Dr. Wan noted. Bone metastases happen when cancer cells travel from the primary tumor site to the bone, establishing a new cancer location. Researchers saw that injecting the miR-34a mimic in mice could prevent the metastasis of breast and skin cancer cells specifically to bone, mainly by disarming the metastatic niche in bone.
“Ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment,” wrote the investigators. “Mechanistically, we identify transforming growth factor-β-induced factor 2 (Tgif2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological, and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers.”
Co-author Joshua Mendell, Ph.D., professor of molecular biology at UT Southwestern and member of the UT Southwestern Harold C. Simmons Cancer Center, noted that his laboratory previously showed that miR-34a can directly suppress the growth of cancer cells.
“We were very excited to see, through this collaborative work with Dr. Wan's group, that miR-34a can also suppress bone metastasis. Thus, miR-34a-based therapy could provide multiple benefits for cancer patients,” said Dr. Mendell.