Home Medizin YAP- und TAZ-Proteine ​​steuern die Knochenentwicklung im Mutterleib

YAP- und TAZ-Proteine ​​steuern die Knochenentwicklung im Mutterleib

von NFI Redaktion


Researchers have identified a pair of proteins, YAP and TAZ, as key players in fetal bone development. Their findings may shed light on genetic diseases such as Osteogenesis imperfecta, commonly known as „brittle bone disease.“ This small-animal research was published today in Developmental Cell and conducted by members of the McKay Orthopedic Research Laboratory at the Perelman School of Medicine at the University of Pennsylvania. The study contributes to a better understanding of mechanobiology, which explores how mechanical forces affect biology.

„Although the mechanobiology of bone development has been studied for over a century, the cellular and molecular foundations have largely remained a mystery. Here, we identify a novel population of cells crucial for the transition of the body’s early cartilaginous template into bone, driven by the force-activated gene regulatory proteins YAP and TAZ.“


Joel Boerckel, PhD, lead author of the study, associate professor of orthopedic surgery

Through combing the genes expressed by individual cells in developing mouse limbs using single-cell sequencing, Boerckel and the study’s first author, former Penn bioengineering doctoral student Joseph Collins, PhD, along with their colleagues, identified and described a class of cells. They named these cells „vascular-associated osteoblast precursors (VOPs),“ which penetrate the early cartilage in addition to blood vessels. Since osteoblasts are the cells responsible for bone formation (and fixation), these cells are essentially the grandparents of bone, with osteoblasts being the parents of bone.

Furthermore, a pair of proteins called YAP and TAZ, which are sensitive to the body’s natural movement – a crucial factor in the early bone development and regeneration, as previously uncovered by the team – serve as guides for the VOPs to integrate signals obtained from the body’s mechanobiology.

The researchers found that YAP and TAZ help regulate the integration of blood vessels into the cartilage, a significant aspect of bone development. They demonstrated this role by first genetically removing YAP and TAZ from human cell models, which evidently halted angiogenesis, the process of forming new blood vessels. Subsequently, the researchers treated these human cell models with a specific type of protein called CXCL12, which restored YAP and TAZ and reinitiated normal angiogenesis.

The study results from a longstanding collaboration with Dr. Niamh Nowlan from University College Dublin, whose lab focuses on how mechanical forces control skeletal development in animal models and in human patients.

It is also pertinent that Boerckel, Collins, and their team utilize their research on bone development as a lens to enhance the understanding of mechanobiology.

„The study of bone development is the birthplace of mechanobiology,“ Boerckel said. „For example, Wolff’s Law of Bone Transformation states that trabecular spongy bone adapts based on loading, but Julius Wolff dedicated more to bone development than trabecular bone in his 1894 book.“

With the insights that the Penn researchers have gained from their study on both bone development and mechanobiology, they believe they can now provide part of the knowledge and, hopefully, the treatment for genetic and congenital musculoskeletal disorders. This includes brittle bone disease, where the body fails to properly produce collagen, causing bones to easily break, and arthrogryposis – a condition where joints fail to develop properly due to limited fetal movement.

„We are now working to use these findings to target these cells and pathways, either through direct mechanical or pharmacological means, to restore cell function and proper bone development in the womb, thus potentially preventing these types of diseases,“ 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).

Source:

Perelman School of Medicine at the University of Pennsylvania

Journal reference:

Collins, JM, et al. (2023). YAP and TAZ couple osteoblast precursor mobilization to angiogenesis and mechanoregulation in mouse bone development. Developmental Cell. doi.org/10.1016/j.devcel.2023.11.029.

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