Decoding NRF1-Mediated Regulation of Osteoclast Metabolism and Bone Turnover

• Applicant: Dr. Carina Scherbel
• Subject Area: Rheumatology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572083681

Bone homeostasis relies on the coordinated activity of osteoclasts (OCs) and osteoblasts (OBs), a balance that is disrupted in diseases such as osteoporosis and autoimmune arthritis. Excessive osteoclastogenesis drives pathological bone resorption, yet the metabolic and mitochondrial underpinnings of OC differentiation and function remain poorly defined. Recent research suggests that osteoclasts undergo profound metabolic reprogramming during differentiation and activation, shifting from oxidative phosphorylation to aerobic glycolysis to meet the energy demands of bone resorption. Mitochondrial performance is therefore crucial for both differentiation and resorptive function. However, the transcriptional regulators linking mitochondrial function to OC biology remain largely undefined. This project addresses a critical gap in osteoimmunology by investigating the role of nuclear respiratory factor 1 (NRF1), a master transcriptional regulator of mitochondrial biogenesis and function, in osteoclast metabolism and bone remodeling. We hypothesize that NRF1 is a central regulator of osteoclast metabolism and bone turnover. To test this, we will employ a combination of genetic, molecular, and imaging-based approaches to dissect how NRF1 influences transcriptional programs, mitochondrial dynamics, and metabolic pathways during osteoclastogenesis. By comparing NRF1-deficient and wild-type osteoclast precursors, we will generate comprehensive transcriptomic and metabolomic profiles to uncover NRF1-dependent networks. Advanced imaging techniques and functional assays will allow us to characterize mitochondrial morphology, oxidative capacity, and energy metabolism in mature OCs. Furthermore, we will assess how NRF1 loss affects bone architecture and remodeling in vivo using µCT, histomorphometry, and serum analysis. Finally, the role of NRF1 in inflammatory bone loss will be evaluated in an arthritis model. This work will uncover novel insights into the transcriptional and metabolic regulation of osteoclasts and identify NRF1 as a potential therapeutic target for bone-destructive diseases. By bridging mitochondrial biology and osteoimmunology, the project aims to open new avenues for treating conditions associated with pathological bone resorption.

• DFG Programme: Research Grants