U of M Musculoskeletal Researcher Hopes to Generate Novel Therapies for Osteoporosis Treatment

Osteoporosis, a condition that causes age-related bone loss, is nearly four times more common in women than men, according to a study published in the Journal of Bone and Mineral Research. One of the outstanding scientific questions is why this occurs more frequently in women as they age.

“It’s a hot topic in the field of musculoskeletal research,” explained Elizabeth Bradley, PhD, a biochemist in the University of Minnesota Medical School’s Department of Orthopedic Surgery. “Our research is examining whether the accelerated period of bone loss during menopause is related to hormones, general aging or a phenomenon that happens concurrently.”

Dr. Bradley developed a keen interest in musculoskeletal health during graduate training at the Mayo Clinic. As the Department of Orthopedic Surgery’s first full-time researcher hired within a decade, her research demonstrates a commitment to improving and better understanding women’s musculoskeletal health. She joined the University in June 2019 to expand research opportunities and interdisciplinary collaboration. Her laboratory is located in the Stem Cell Institute, providing her with access to state-of-the-art equipment and high-level researchers. 

“Dr. Bradley has been an outstanding addition to the University's research scientists,” said Joan Bechtold, PhD, vice chair of research in the Department of Orthopedic Surgery. “She has demonstrated a commitment to scholarship, critical thinking and has a curious mind. We look forward to her building her program here.”

She partnered with Kim Mansky, PhD, professor in the School of Dentistry, and Kristin Hogquist, PhD, professor in the Department of Laboratory Medicine and Pathology, to submit an osteoporosis-related research proposal to the Medical School’s Seed Grants for Interdisciplinary Research on Aging in Women. They were recently awarded the grant, which supports research to improve the health and wellbeing of menopausal and postmenopausal women.

“This research will begin to address the mechanisms that regulate age-related bone changes in women,” Dr. Mansky said.

Dr. Bradley’s preliminary work was awarded a National Institutes of Health grant to examine protein phosphatase (Phlpp1), which controls bone resorption (a process where osteoclasts break down bone to maintain blood calcium levels). If osteoclasts break down bone faster than it can be repaired, bone mass loss-related diseases like osteoporosis may arise.

“We develop tiny microfractures in our bones from everyday activities, which are continuously repaired during a bone remodeling cycle,” Dr. Bradley explained. “Cells that resorb bone remove the microfractures and produce coupling factors that attract osteoblasts (bone forming cells) to fill in the removed area.”

In healthy, young people, the process of removing microfractures and building new bone is generally balanced, so there isn’t a significant loss in bone mass. In contrast, coupling factors that attract osteoblasts are disrupted with age, resulting in bone loss.

Dr. Bradley and her team are exploring how the Phlpp1 gene promotes coupling factors, which are critical to maintaining bone mass. She discovered that deleting Phlpp1 from mice osteoclasts led to increased bone formation and mass.

“Researchers are working to enhance the coupling process so that factors created by the resorbing cells increase bone forming cells,” she said. “The Phlpp1 gene has been shown to promote coupling, which could lead to new ways to increase bone mass.”

Although the cells that break down bone increased in number, Phlpp1 deficiency increased bone-coupling factors, regulated osteoclasts and increased bone mass.

“Targeting Phlpp1 could lead to alternative therapies for osteoporosis prior to and after the accelerated phase of loss after menopause or age-associated bone loss,” she added.

She also found that Phlpp1 levels decline in bone biopsies as women age but could be restored using short-term estrogen therapy, which could lead to novel treatments for women with osteoporosis.

The other aspect of her research focuses on two chromatin modifiers (proteins that can add, interpret and delete histone modifications) of the enzyme histone deacetylase (Hdac3) and its impact on skeletal health. When her team removes the Hdac3 gene from mice, macrophage cells (white blood cells that remove foreign particles) are produced. Macrophages come in various forms. M1 macrophages lead to an inflammatory response and are signaled to the site of an injury. This initial inflammation helps clear infection and leads to better healing, however, if unbalanced, it can also cause tissue necrosis. M2 macrophages, on the other hand, possess anti-inflammatory and anti-thrombotic properties to help repair tissue during healing.

In young, healthy people, production of both M1 and M2 macrophages is typically balanced. However, there’s a shift towards producing more M1 inflammatory macrophages with age, which can deter healing.

“There’s a term called ‘inflammaging’ which refers to increased inflammatory responses as we age,” Dr. Bradley said. “While most fractures heal, delayed or nonunions become more prevalent with age. Conditions like diabetes may also decrease fracture healing.”

The team’s data suggest that Hdac3 limits inflammatory responses and promotes skeletal healing in females.

“When we delete Hdac3, we can skew production towards the M2 anti-inflammatory macrophages,” Dr. Bradley said. “If the mouse has an injury to their cortical bone, they heal better if they don’t have the Hdac3 gene.”

Dr. Bradley hopes that existing clinically approved Hdac inhibitors could be used to develop new therapies to balance M2 macrophage production and promote healing in patients with osteoporosis.