Overview
Dr. Novince’s research defined a novel inter-organ signaling pathway linking the gut microbiota to skeletal homeostasis.
This project tested the hypothesis that microbial-derived signals stimulate MyD88-dependent innate immune pathways in the liver, leading to production of circulating factors that regulate bone remodeling.
The work established a gut–liver–bone axis in which commensal microbiota enhance osteoclast activity and suppress osteoblast function, promoting bone loss. These studies addressed a major gap in understanding the mechanisms underlying early adult bone deterioration and provided a new paradigm connecting microbiome-derived immune signaling to skeletal biology.
Specific Aims
- Define how gut microbiota activates hepatic MyD88-dependent innate immune signaling and production of systemic factors
- Determine how liver-derived lipocalin-2 (LCN2) regulates osteoclastogenesis and osteoblastogenesis
Research Approach
The project combined germ-free and conventional mouse models with cell-specific genetic manipulation to dissect liver immune signaling pathways. Hepatocyte- and myeloid-specific MyD88 knockout models were used to define how microbial signals activate liver innate immunity. Multi-tissue analyses quantified cytokines, acute phase proteins, and microbiome composition. Functional studies of bone remodeling incorporated micro-CT imaging, histomorphometry, and in vitro osteoblast and osteoclast assays. Mechanistic focus was placed on the acute-phase protein LCN2 as a systemic mediator linking liver immune activation to bone cell function.
Use of the Center's Core Resources
Gnotobiotic Animal Facility
- Germ-free and microbiota-controlled mouse studies
Advanced Imaging Core
- Tissue imaging and bone analysis
Biostatistics and Genomics Cores
- 16S sequencing and integrative data analysis
Innovation
- Introduces the gut–liver–bone axis as a novel regulator of skeletal biology
- Identifies liver-derived innate immune factors as mediators of microbiome effects on bone
- Defines lipocalin-2 as a key systemic regulator linking inflammation and bone remodeling
Impact and Outcomes
This project provides a conceptual shift from direct gut–bone signaling to a multi-organ immune axis controlling skeletal remodeling. By identifying liver-derived factors such as LCN2 as mediators of microbiome-driven bone loss, this work established a foundation for novel therapeutic strategies targeting microbiota, liver immunity, or systemic inflammatory pathways to prevent osteoporosis.
Participation in the
Center for Biomedical Research Excellence in Digestive & Liver Disease's program supported Dr. Novince’s transition to independence and established his research program at the intersection of immunology, microbiology, and bone biology.
