Deciphering the physiological function(s) of Panx3, a gene displaying specific expression in bone-forming osteoblasts

• Applicants: Professor Johannes Keller, Ph.D.; Professor Thorsten Schinke, Ph.D.
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 492686146

Bone formation mediated by osteoblasts is essential for development, growth, remodeling and regeneration of the skeleton. This process depends on the provision of large amounts of energy, and osteoblasts were recently found to rely mostly on glucose availability. Moreover, genetic evidence obtained in the last two decades has clearly demonstrated that bone is also an endocrine organ, and that osteoblast lineage cells release hormonal regulators of serum phosphate and glucose homeostasis. The relevance of energy metabolism regulation by osteoblast-derived molecules is however still debated, and the underlying complexities are still not fully understood.We have previously identified a potential role of Pannexin-3 (Panx3), a transmembrane protein predominantly expressed by osteoblasts, in linking bone formation to energy metabolism. In particular, we could demonstrate that Panx3 deficiency in neonatal mice not only results in impaired skeletal development, but also in hypoglycemia. Additional experiments revealed that Panx3-deficient osteoblasts display higher intracellular ATP levels, potentially mimicking energy excess and reducing expression of metabolically relevant genes. Another key finding was that Panx3-deficient neonates displayed a higher hepatic glycogen content despite absence of Panx3 expression in the liver. Finally, we could identify Panx3 to be relevant for bone regeneration, a process found associated with alterations in blood glucose levels and metabolic marker expression in liver and adipose tissue.Collectively, our findings strongly suggest that Panx3 deficiency impairs osteoblast activity in states of excessive bone formation, i.e. during skeletal development/growth and fracture healing and that Panx3 deficiency additionally impacts glucose homeostasis by altering metabolic functions of the liver. Since our previous data also raise several questions, we now intend to perform additional analyses to define the molecular functions of Panx3 in skeletal development and energy metabolism. First, we will perform in depth-phenotyping of mice lacking Panx3, ubiquitously or only in specific cell types, during skeletal development and growth. Second, since we did not detect major abnormalities in adult Panx3-deficient mice, we will challenge them by different means, which includes genetic activation of bone formation, but also induction of bone regeneration. Third, in order to understand the molecular bases of the observed phenotypes we will analyze primary wildtype and Panx3-deficient cells, which includes unbiased transcriptomic approaches.

• DFG Programme: Research Grants
• International Connection: Canada
• Cooperation Partner: Professorin Dr. Silvia Penuela