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Their analysis of genetically altered mice during a 15-year time frame found that BMPs are involved in virtually every aspect of cartilage cell (chondrocyte) formation, differentiation, and survival and that different BMP receptors have both overlapping and unique functions in cartilage.

AAOS Now

Published 3/1/2008
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Eileen Norris

Defining BMP action in cartilage

Drs. Lyons and Rosen win Ann Doner Vaughan Award

Karen M. Lyons, PhD, and Vicki Rosen, PhD, have received the 2008 Kappa Delta Ann Doner Vaughan Award for their research and manuscript on “In Vivo Studies of BMP Pathway Activities in Chondrogenesis.” Their honor caps nearly two decades of efforts to better understand the underlying roles of bone morphogenetic protein (BMP) action in cartilage, and also reveals previously undiscovered aspects of chondrocyte behavior in vivo.

Karen M. Lyons, PhD

“These insights suggest new avenues to enhance the efficacy of therapies using BMPs for cartilage regeneration and fracture repair,” they wrote. “Understanding the precise roles of different BMPs and their receptors will hopefully allow more appropriate selection of specific BMPs to promote specific actions in cartilage clinically,” added Dr. Lyons.

Finite perspective
Historically, BMPs were thought to play critical roles in cartilage formation because they have the ability to induce ectopic cartilage and are expressed in dynamic patterns. But when the authors began their studies, little data addressed whether different BMPs and their receptors had different functions. The precise roles of BMP pathways in cartilage during development were also unknown. By examining the consequences of the loss of specific BMP ligands (and combinations of ligands), the researchers found a considerable amount of combinatorial activity.

Different combinations of BMPs control the formation of specific bones. Investigating the functions of BMP receptors revealed that BMPs are essential for every aspect of chondrocyte commitment and differentiation. “BMPs are involved in every aspect of cell formation,” said Dr. Lyons. The team’s research provided genetic evidence to refute earlier suggestions that different BMP receptors transduce fundamentally different signals. The authors discovered that each BMP type 1 receptor has some unique functions, raising the possibility that strategies may be developed in which specific BMP receptors may be targeted for specific applications.

Furthermore, their studies demonstrated that antagonistic interactions between BMP and fibroblast growth factor (FGF) pathways regulate most aspects of chondrocyte behavior in the growth plate. “One of our key findings was that loss of the receptor BMPR1A leads to knee osteoarthritis, so we know BMPs must play a central role in articular cartilage,” said Dr. Lyons. “Understanding the exact roles of BMPs will hopefully lead to more effective uses of BMPs clinically. Now that the importance of BMPR1B in articular cartilage is known, it may be possible to use BMPs that specifically interact with this receptor to treat osteoarthritis,” she added.

Clinical potential
According to the latest report from the Centers for Disease Control and Prevention, the number of people affected by arthritis will increase 16 percent by the year 2030, making arthritis the nation’s leading cause of disability. Because osteoarthritis is the most prevalent form of arthritis, understanding how BMP pathways maintain the chondrocyte phenotype during development is vital to understanding how to improve the maintenance of the articular chondrocyte phenotype in adults.

“Numerous studies have investigated the effects of BMPs on articular chondrocytes in vitro, and these have reported conflicting results, probably due to the use of different cell types, growth regimens, experimental endpoints, and the propensity of these cells to dedifferentiate. However, these studies concur in that BMPs are potent stimulators of chondrocyte proliferation and differentiation, and that they can promote ex vivo articular cartilage formation,” wrote the researchers.

A more general clinical problem that these studies address is the requirement for high doses of BMPs in fracture healing protocols. “We know that very large doses of BMPs are required in fracture healing protocols in humans, but if we knew more about which BMP signaling pathways are important, perhaps BMP efficacy could be improved. That will help us to develop more effective and targeted therapies,” said Dr. Lyons.

Their studies showed that FGF and BMP pathways act antagonistically, suggesting that BMP efficacy might be improved by the concurrent administration of FGF inhibitors. “Perhaps concurrent administration of FGF inhibitors and BMPs would increase the potency of BMPs,” she said “Both pharmacological and naturally occurring secreted inhibitors exist and could be contemplated for this purpose.”

Initial Studies
Drs. Lyons and Rosen began their collaborative work in 1994, studying the roles of BMPs in cartilage and bone formation during development. A series of collaborative studies of BMP expression led to the discovery that BMP3 is a negative regulator of bone formation. They participated in the original cloning of BMP receptors, and in the generation and analysis of BMPR1B-deficient mice. “This work,” they explained, “was the nucleus for the detailed studies of the function of other BMP receptors and the Smads in the growth plate.”

Future studies
“We want to look at the intracellular pathways that are activated by BMPs,” said Dr. Lyons about future studies. “For example, we need to identify specific genes whose activity is controlled by BMPs. We also want to learn more about the role of BMPs in osteoarthritis. And we want to answer questions, such as is the osteoarthritis that develops in BMPR1B mutants due to a defect in the shape of the cartilage surface that leads to excessive wear on the cartilage, and/or is BMPR1B required directly in adult articular cartilage cells? We hope to see the full breadth of our research realized within the next decade,” she added.

Dr. Lyons’s work was funded by research grants from the American Heart Association and the National Institutes of Health. She is listed as an inventor on a patent involving BMP3, held by Wyeth (US Patent 6432919), but Dr. Lyons does not have any industrial and commercial interests. Dr. Rosen’s work was supported by research grants from the National Institutes of Health and the Musculoskeletal Transplant Foundation. As a result of her prior position as Director of Musculoskeletal Sciences at Genetics Institute, Cambridge, MA, she holds numerous patents, but currently has no industrial or commercial interests.

Eileen Norris is a freelance writer specializing in healthcare issues.

An historic cycle?
Drs. Lyons and Rosen began studying the roles of bone morphogenetic proteins (BMPs) in cartilage and bone formation during development in 1994. BMPs were discovered by the late Marshall Urist, MD, who was a faculty member at University of California, Los Angeles (UCLA), where Dr. Lyons currently is a professor in the UCLA/Orthopaedic Hospital department of orthopaedic surgery, and in the department of molecular, cell, and developmental biology.

Dr. Urist, who received the first Kappa Delta award in 1950 (see story on page 12), won a second Kappa Delta award in 1981 for the discovery of BMPs. Drs. Lyons and Rosen both enjoyed a close relationship with him. “Dr. Urist was very supportive of our work, so it is gratifying to bring this award based on BMP work to UCLA again,” said Dr. Lyons.