Bone Marrow Fat Drives Obesity-Related Bone Loss

Obesity affects bone health not only through body weight but also by changing the bone marrow environment. In a recent study, researchers showed that expansion of bone marrow fat promotes an immunosuppressive PD-L1 signaling pathway that increases osteoclast formation and speeds bone loss. Reducing bone marrow fat in mice lowered immune suppression and improved bone structure, pointing to a mechanism that connects metabolism, immunity, and skeletal health.

The work was led by Clifford J. Rosen and Sergey Ryzhov at the Center for Molecular Medicine, MaineHealth Institute for Research, and was published in Bone Research. The team used diet-induced obese mouse models, cellular co-culture systems, and genetic depletion models to study how bone marrow adipocytes interact with immune cells and osteoclast precursors.

The researchers found that obesity caused a rapid and persistent increase in bone marrow fat. This fat expansion changed the molecular profile of adipocytes and increased production of signaling molecules such as MCP-1, which recruits and reshapes myeloid immune cells. As a result, PD-L1-expressing myeloid cells accumulated in the bone marrow. These cells suppressed T-cell activity and created an immunosuppressive environment that disrupted immune balance. They also directly affected osteoclast development.

The study showed that PD-L1-expressing myeloid cells interact with PD-1 receptors on osteoclast precursors, promoting their maturation into osteoclasts. This increased bone resorption and reduced trabecular and cortical bone volume. Blocking the PD-1/PD-L1 pathway early in osteoclast formation reduced both the number and activity of these bone-resorbing cells, underscoring its role in osteoclastogenesis. As Dr. Rosen explained, “We discovered that bone marrow fat is not simply a passive tissue but actively reshapes immune signaling in ways that accelerate bone loss in obesity.”

To confirm the findings, the researchers studied mice genetically modified to lack bone marrow adipocytes. These mice had lower MCP-1 levels, fewer PD-L1+ immune cells, and fewer osteoclast precursors. They also showed improved bone structure and less bone resorption, even when obese. Dr. Ryzhov added, “This immune checkpoint pathway, known for regulating T-cell responses, also directly drives osteoclast formation, revealing a completely new link between immunity and skeletal health.”

The findings suggest possible new strategies for protecting bone health in obesity by targeting bone marrow fat or immune checkpoint pathways. They may also help explain obesity-related immune problems, including reduced vaccine effectiveness and higher infection risk.