YAP and TAZ proteins guide bone growth in utero

A pair of proteins, YAP and TAZ, have been identified as conductors of bone growth in utero and could provide insights into genetic diseases such as osteogenesis imperfecta, commonly known as ‘brittle bone disease’. This small animal-based research, published today in Developmental Cell and led by members of the McKay Orthopedic Research Laboratory at the Perelman School of Medicine at the University of Pennsylvania, adds understanding to the field of mechanobiology, which studies how mechanical forces affect biology.

Despite more than a century of study of the mechanobiology of bone development, the cellular and molecular basis has remained largely a mystery. Here, we identify a new cell population that is key to converting the body’s early cartilage template into bone, driven by the force-activated gene-regulating proteins, YAP and TAZ.’

Joel Boerckel, PhD, senior study author, associate professor of Orthopedic Surgery

By combing through single-cell sequencing for genes expressed by individual cells in developing mouse limbs, Boerckel and the study’s first author, former Penn Bioengineering doctoral student Joseph Collins, PhD, along with colleagues, found and described a class of cells which they termed “vessel-associated osteoblast progenitors (VOPs)” that “invade” early cartilage alongside blood vessels. Since osteoblasts are the cells required for the formation (and fixation) of bone, these cells would essentially be the grandparents of bone, with osteoblasts being the parents of bone.

And, crucially, a pair of proteins called YAP and TAZ that are sensitive to the body’s natural movement—which the team’s previous work has shown is crucial for early bone growth and regeneration—serve as guides for the VOPs, transmitting signals they collect from the body’s mechanobiology.

The researchers found that YAP and TAZ help direct the integration of blood vessels into cartilage, a vital aspect of bone development. They were able to demonstrate this role by first genetically removing YAP and TAZ from human cell models, which appeared to stop angiogenesis, the process by which new blood vessels form. The researchers then 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 long-term collaboration with Dr Niamh Nowlan of University College Dublin, whose laboratory focuses on how mechanical forces direct skeletal growth in animal models and human patients.

It is also appropriate that Boerckel, Collins and their team use the exploration of bone development as a lens to advance 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-cancellous-bone adapts in a manner proportional to the stresses placed on it, but Julius Wolff spent more time in his 1894 book focusing on the development of bone rather than trabecular bone. “

With the information the Penn researchers gleaned from their study of both bone development and mechanobiology, they believe they can now inform some of the knowledge and, hopefully, treatment of genetic and congenital musculoskeletal disorders. 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 the joints develop improperly due to limited fetal movement.

“We are now working to use these findings to target these cells and pathways, either by direct mechanical or pharmacological means, to restore cellular function and proper bone growth in utero, potentially preventing these types of conditions,” he said. Boerckel.

This research was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR073809, R01 AR074948, P30AR069619, NSF CMMI 1548571) and the European Research Council (336306).