How Does the Skeletal System Work With the Immune System?
Explore the connection between the skeletal and immune systems, including how bone marrow supports immunity and how these systems interact over time.
The skeletal and immune systems may seem distinct, but they are deeply interconnected. Beyond providing structural support, bones house bone marrow, where immune cells develop. This relationship enables the body to respond to infections and other threats.
Research has revealed complex interactions between bone and immune cells that influence overall health. These connections evolve with age and contribute to diseases like osteoporosis and arthritis. Understanding this interplay sheds light on immune-related bone conditions.
Bone Marrow And Immune Cell Production
Bone marrow, a specialized tissue inside bones, is the primary site for immune cell formation. It exists in two forms: red and yellow marrow. While yellow marrow stores fat, red marrow generates blood cells crucial for immune defense. In early life, red marrow is widespread, but with age, it becomes concentrated in the sternum, pelvis, and vertebrae, reflecting changing immune demands.
Hematopoietic stem cells (HSCs) in red marrow give rise to myeloid and lymphoid progenitors. Myeloid progenitors develop into neutrophils, monocytes, and dendritic cells, key players in innate immunity. Lymphoid progenitors generate T cells, B cells, and natural killer (NK) cells, essential for adaptive immunity. Their development is regulated by stromal cells, cytokines, and growth factors within the bone marrow microenvironment.
Specialized stromal cells, including osteoblasts and mesenchymal stem cells, support immune cell development by secreting signaling molecules. Interleukin-7 (IL-7) aids lymphocyte maturation, while granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes myeloid cell proliferation. Disruptions in these pathways can lead to immune deficiencies or blood disorders, highlighting the delicate balance required for proper function.
Communication Between Bone Cells And Immune Cells
Bone and immune cells constantly exchange signals that influence skeletal integrity and immune function. Osteoblasts and osteoclasts regulate immune activity through cytokine secretion and cell interactions. The receptor activator of nuclear factor kappa-B ligand (RANKL), produced by osteoblasts, binds to RANK on osteoclast precursors, driving bone resorption. Activated T cells also express RANKL, linking bone remodeling to immune responses.
Osteoblasts secrete interleukin-6 (IL-6) and transforming growth factor-beta (TGF-β), which affect immune cells. IL-6 promotes B cell differentiation and T cell activation, while TGF-β suppresses excessive inflammation and supports regulatory T cells. Osteoclasts release tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), which enhance immune responses but, when dysregulated, contribute to inflammatory bone loss. This bidirectional communication ensures a balance between bone remodeling and immune function.
The bone marrow microenvironment amplifies these interactions through mesenchymal stem cells (MSCs), which regulate immune responses by suppressing T cell proliferation and controlling macrophage activity. They also influence osteogenesis by producing vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs), maintaining both bone formation and immune function.
Changes In Skeletal-Immune Interactions With Age
With age, skeletal-immune interactions shift, affecting bone maintenance and immune regulation. Red marrow, which supports immune cell production, gradually converts to yellow marrow, reducing hematopoiesis. This decline contributes to immunosenescence, a gradual weakening of immune function. Aging also diminishes hematopoietic stem cell (HSC) regenerative capacity, lowering lymphocyte output and impairing bone homeostasis.
Bone remodeling dynamics also change. In youth, osteoblast and osteoclast activity are balanced, maintaining bone density. With age, osteoblast function declines while osteoclast activity remains stable or increases, leading to bone loss. Chronic low-grade inflammation, or “inflammaging,” exacerbates this imbalance. Pro-inflammatory cytokines like TNF-α and IL-6 accelerate bone resorption and hinder osteoblast differentiation, weakening bones. Aging-related changes in mesenchymal stem cells (MSCs) further reduce their ability to support bone formation, increasing skeletal fragility.
Examples Of Immune-Related Bone Conditions
Some bone diseases arise from immune system disruptions that affect bone formation and resorption. Rheumatoid arthritis (RA) exemplifies this, as an overactive immune response triggers chronic joint inflammation. This inflammatory environment promotes osteoclast activation through TNF-α and interleukin-17 (IL-17), accelerating bone erosion and joint damage. Disease-modifying anti-rheumatic drugs (DMARDs) help slow progression.
Osteoporosis, though primarily linked to aging and hormones, has immune-related variants. Postmenopausal osteoporosis is influenced by increased IL-6 levels, which enhance osteoclast activity. Glucocorticoid-induced osteoporosis, another immune-driven condition, results from prolonged corticosteroid use, which suppresses osteoblast function while prolonging osteoclast survival. Preventive strategies like bisphosphonates or monoclonal antibodies such as denosumab help mitigate fracture risk.