A pair of proteins, YAP and TAZ, have been identified as drivers of bone development in the uterus and may provide insight into genetic diseases such as osteogenesis imperfecta, commonly known as “brittle bone disease.”
This research based on small animals, published in Development cell and led by members of the McKay Orthopedic Research Laboratory at the University of Pennsylvania Perelman School of Medicine, adds knowledge to the field of mechanobiology, which studies how mechanical forces influence biology.
“Despite more than a century of study on the mechanobiology of bone development, the cellular and molecular basis remains largely a mystery,” said the study’s lead author, Joel Boerckel, Ph.D., professor associate professor of orthopedic surgery. “Here, we identify a new population of cells that play a key role in transforming the body’s first model of cartilage into bone, guided by the force-activated gene regulatory proteins YAP and TAZ.”
By combing through the genes expressed by individual cells in the developing mouse limbs, using single-cell sequencing, Boerckel and the study’s first author, former Penn Bioengineering doctoral student Joseph Collins, Ph.D., along with their colleagues, found and described a class of cells they named “vessel-associated osteoblast precursors (VOPs)” that “invade” early cartilage along blood vessels.
Since osteoblasts are the cells necessary for the formation (and fixation) of bones, these cells would essentially be the grandparents of bones, with osteoblasts being the parents of bones.
And, most importantly, a pair of proteins called YAP and TAZ, responsive to the body’s natural movements (which the team’s previous work has shown are essential for early bone development and regeneration), serve as guides the VOPs, transmitting the signals they glean from the body’s mechanobiology.
Researchers found that YAP and TAZ help direct the integration of blood vessels into cartilage, a critical aspect of bone development. They were able to demonstrate this role by genetically deleting YAP and TAZ from human cell models, which appeared to stop angiogenesis, the process by which new blood vessels form. Next, the researchers treated these human cell models with a special variety of protein called CXCL12, which restored YAP and TAZ and restarted normal angiogenesis.
The study is the result of a long-standing collaboration with Dr Niamh Nowlan of University College Dublin, whose laboratory focuses on how mechanical forces drive skeletal development in animal models and patients humans.
It is also appropriate that Boerckel, Collins and their team use their exploration of bone development as a perspective to deepen the understanding of mechanobiology.
“The study of bone development is the birthplace of mechanobiology,” Boerckel said. “For example, Wolff’s law of bone transformation says that trabecular – spongy – bone adapts in a way depending on the stresses placed on it, but Julius Wolff devoted more time in his 1894 book to the development bone than trabecular bone.”
With the information the Penn researchers gained from their study of bone development and mechanobiology, they believe they can now shed light on some knowledge and, hopefully, treatment of genetic and congenital musculoskeletal diseases. This includes brittle bone disease, in which the body does not produce collagen properly, causing bones that can break easily, or arthrogryposis, a condition in which joints do not develop properly due to limited fetal movement.
“We are currently working to use these findings to target these cells and pathways, either through direct mechanical or pharmacological means, to restore cellular function and proper bone development in utero, potentially preventing these types of conditions.” , Boerckel said.
More information:
Joseph M. Collins et al, YAP and TAZ link osteoblast precursor mobilization to angiogenesis and mechanoregulation in murine bone development, Development cell (2023). DOI: 10.1016/j.devcel.2023.11.029
Provided by the Perelman School of Medicine at the University of Pennsylvania
Quote: YAP and TAZ: protein partners identified as potential keys to fetal bone development (January 4, 2024) retrieved January 4, 2024 from
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