Current Projects
Leveraging mice with natural microbial exposures to redefine osteoporosis pathogenesis
Premise: Specific pathogen-free (SPF) mice lack exposure to pathogenic and commensal microbes and form the foundation of biomedical research. If you do work with laboratory animals, the chances are extremely high that they are SPF. Recent work from immunology (e.g. Beura et al. 2016 in Nature, Hamilton et al. 2020 in J Clin Immunol) and microbiology (e.g. Rosshart et al. 2019 in Science) have called into question the utility of the SPF model, as microbial exposures robustly impact the immune system and therefore, broader host physiology. Unlike immune naïve SPF mice, mice with natural microbial exposures (NME; e.g. wild or pet store mice) are immune mature, demonstrating chronic immune activation and paralleling basal inflammatory responses seen in humans.
Bone-Immune Link: Bone and the immune system are intricately linked, particularly in the bone marrow microenvironment where immune cells are housed and generated. Microbial exposures activate immune cells (e.g. T cells), which then produce inflammatory cytokines (e.g. TNFa, IFNy, interleukins, etc.) to coordinate the immune response. Both immune cells and their inflammatory cytokines are major regulators of bone and bone cells, including osteoblasts and mesenchymal stem cells.
NME mice have significantly elevated levels of over 20 inflammatory cytokines known to critically mediate bone homeostasis, indicating the cell signaling environment in NME mice is primed to fundamentally alter bone homeostasis relative to an immune naïve animal – see the image for a visual summary. For a detailed explanation of the NME mouse and historical context of the field of osteoimmunology, see Little-Letsinger & Hamilton 2023 in Frontiers in Endocrinology.
Current Status: This work is on-going! Our efforts are primarily related to how host defense impacts bone homeostasis across the lifespan with the goal to redefine osteoporosis pathogenesis by incorporating the immune and reproductive systems. While this is our primary goal, our interests are broad and we are always looking for new collaborations!
Future Directions: Future work with the NME mouse includes, but is not limited to the following.
- Explore the utility of the NME model for bone marrow metastases
Dissecting behavioral and environmental factors influencing the evolution of the skeleton
Premise: The skeleton of modern humans is gracile, demonstrating reduced cortical and trabecular bone mass and strength, relative to earlier human ancestors. Such skeletal gracilization is likely responsible for the unique propensity of humans to experience osteoporotic fractures. The behavioral, environmental, and physiological factors that drove skeletal gracilization and the resulting divergence in fractures between humans and our ancestors remain unknown.
Connecting to the Neolithic: Skeletal gracilization begins with the onset of the Holocene, and specifically the Neolithic period. The Neolithic is strongly associated with the transition from foraging to subsistence farming that ultimately led to permanent dwellings, domestication of livestock, and massive increases in population density. Current hypotheses regarding skeletal gracilization posit that physical inactivity was the primary driver (e.g. see work from Ruff, Chirchir, Ryan and others). However, data demonstrate that skeletal gracilization has stabilized from the Neolithic through to the 20th century. Given the effects of industrialization and record high rates of physical inactivity among the current population, further gracilization would be expected if physical inactivity were the primary driver.
The Neolithic is also considered to be a “turning point” in the evolution of the immune system (Dominguez-Andres et al. 2021 in eLife). Sustained increases in population density, poor sanitary conditions, and greater contact between humans and animals enabled robust increases in infectious and zoonotic diseases. Among modern day subsistence farming communities with high rates of physical activity, those communities with high infectious disease burden demonstrate bone loss and fracture rates that exceed that of US citizens, despite the absence of risk factors common in industrialized society. When considering the importance of the immune system for regulation of bone homeostasis, the rise in infectious disease burden during the Neolithic is a promising avenue to understand skeletal gracilization. For a detailed explanation of the role of infectious disease in controlling bone homeostasis in the evolution of the human skeleton, see Little-Letsinger & Hamilton 2023 in Frontiers in Endocrinology.
Current Status: This work is on-going! Our efforts are primarily related to artificial selection relating to immune exposures (using the NME mouse described above) and physical inactivity. We are focused on the trade-offs within and across systems, considering the skeletal, immune, and reproductive systems. If this work excites, please do not hesitate to reach out as we are always looking for new collaborations!
Future Directions: Future work with the NME mouse includes, but is not limited to the following.
- Explore the future evolution of bone in the context of adapting to a multi-planetary existence
Overview of Future Directions:
Future projects are always under consideration, and include, but are not limited to:
- Bone health in space flight – considering microgravity and/or radiation
- How aging of the immune system impacts bone health
- Sex hormone-regulation of bone health in adolescence and post-menopause
- Dietary regulation of bone health – including diet-induced obesity and caloric restriction
- Effect of habitual movement patterns on bone strength and structure
- Others….
We are always eager to discuss new or existing ideas and directions with interested parties!