NIBB-Academia Sinica International Webinar of Aquatic Model Organisms for Basic Biology to Human Disease Models

Speaker: Dr. Christoph Winkler

Institute: Department of Biological Sciences, National University of Singapore, Singapore

Talk title: Osteoblasts control osteoclast recruitment and activation in a medaka osteoporosis model

Bone homeostasis requires continuous remodeling of bone matrix to maintain structural integrity. This involves extensive communication between bone-forming osteoblasts and bone-resorbing osteoclasts to orchestrate balanced progenitor cell recruitment and activation. Only few mediators controlling progenitor activation are known to date and have been targeted for intervention of bone disorders such as osteoporosis. To identify new druggable pathways, we used a medaka (Oryzias latipes) model, where inducible expression of Receptor activator of nuclear factor kappa-Β ligand (Rankl) leads to ectopic formation of osteoclasts, excessive bone resorption and osteoporosis-like lesions. Using live imaging, we show that upon Rankl induction a distinct subset of macrophages is recruited to bone matrix. There, the macrophages physically interact with bone forming osteoblast progenitors and differentiate into osteoclasts. Later, other macrophages are recruited to clear dying osteoclasts from resorbed bone by phagocytosis. To better understand the molecular changes underlying these dynamic processes, we performed transcriptome profiling of osteoblast progenitors and activated macrophages upon Rankl induction. This revealed upregulation of the chemokine ligand Cxcl9l in osteoblasts and the chemokine receptor Cxcr3.2 in activated macrophages. We show that both are essential to control osteoclast progenitor recruitment and differentiation at bone resorption sites. Cxcr3.2 activity can be blocked by small molecule inhibitors that protect bone from osteoporotic insult. Surprisingly, we also identified upregulation of osteoblast-promoting signals in Rankl-activated macrophages, suggesting possible non- cell autonomous roles in bone repair and osteogenesis. Our study demonstrates the potential of fish for osteoporosis drug discovery and reveals complex cellular interactions that control bone homeostasis.