The skeletal system provides structure, support, and protection for internal organs. The immune system is the body’s defense network, responsible for surveillance and eliminating foreign invaders such as bacteria and viruses. While seemingly distinct, these two systems are deeply interconnected, constantly communicating through shared cellular origins and complex molecular signals. The health of one system directly influences the other, blurring the traditional boundaries between bone biology and immunology.
The Bone Marrow: Immune Cell Factory
The fundamental link between the skeletal and immune systems lies within the bone marrow, the soft, spongy tissue found inside bones. This tissue functions as the primary factory for blood and immune cells, a process termed hematopoiesis. Every circulating immune cell—from lymphocytes (T-cells and B-cells) to myeloid cells (neutrophils, macrophages, and monocytes)—origines from hematopoietic stem cells (HSCs) residing here.
In adults, active blood production takes place mainly in the red bone marrow, concentrated in the axial skeleton, including the skull, ribs, sternum, and vertebrae. As individuals age, the red marrow in the long bones is largely replaced by fatty, inactive yellow marrow. The production process is tightly regulated, generating 100 billion new blood cells daily to replace those lost or destroyed while fighting pathogens.
Hematopoietic stem cells are maintained in a specialized microenvironment within the bone marrow known as the hematopoietic niche. This niche is composed of various bone-related cells, including osteoblasts and stromal cells, which provide the molecular cues needed to control stem cell self-renewal and differentiation. During infection or inflammation, this production line is dynamic, quickly escalating to meet demand by driving stem cells to differentiate rapidly into myeloid cells like neutrophils and monocytes to mount an effective defense.
Immune Regulation of Bone Structure
The interconnectedness extends beyond cell production, as the immune system actively regulates the continuous breakdown and rebuilding of bone tissue, a process called bone remodeling. This cross-regulation established the scientific field of osteoimmunology. Bone structure is maintained by a balance between two specialized cell types: osteoblasts, which form new bone tissue, and osteoclasts, which resorb (break down) old bone tissue.
Immune cells directly influence this balance by controlling the activity of osteoclasts, which share a common origin with macrophages and monocytes. A protein called Receptor Activator of Nuclear factor Kappa B Ligand (RANKL) is a potent stimulator of osteoclast formation and activity. Immune cells, particularly activated T-cells, are a major source of RANKL, linking immune responses directly to bone resorption.
The immune system also produces factors that inhibit bone breakdown. For example, Interferon-gamma (IFN-\(\gamma\)), a cytokine released by T-cells, acts as a brake on osteoclast activity, protecting the bone from excessive resorption. Pro-inflammatory cytokines, such as Tumor Necrosis Factor-alpha (TNF-\(\alpha\)) and various Interleukins (IL-1, IL-6, IL-7), released during an immune response, can stimulate osteoclast formation and inhibit osteoblast function, promoting bone loss.
Chemical Communication Between Systems
The skeletal system is not a passive structure; it acts as an endocrine organ, releasing chemical messengers that circulate throughout the body and influence the immune system and metabolism. This highlights a systemic regulatory loop originating from the bone. Bone cells, particularly osteoblasts, produce a hormone called Osteocalcin (OCN).
Osteocalcin is released into the bloodstream, especially its undercarboxylated form, during active bone turnover. While known for its role in regulating glucose metabolism by increasing insulin secretion and sensitivity, it also contributes to the systemic regulatory loop. Research suggests that bone-derived factors like Osteocalcin may influence immune cell function, demonstrating the skeleton is involved in regulating systemic health beyond its structural role.
This systemic signaling from bone contrasts with the local control exerted by immune cells on bone remodeling. Other factors secreted by bone cells, such as the cytokine Interleukin-6 (IL-6), also act as messengers. IL-6 is produced by osteoblasts and stromal cells and influences the immune environment, establishing bone as an active participant in systemic communication.
When The Crosstalk Fails
The balance between the skeletal and immune systems is evident when their communication breaks down, leading to pathology. A clear example is seen in autoimmune diseases like Rheumatoid Arthritis (RA). In RA, chronic inflammation and aberrant immune activation lead to excessive bone erosion.
Immune cells within the inflamed joints produce inflammatory cytokines, including TNF-\(\alpha\) and IL-17, which strongly stimulate osteoclast activity. This leads to localized bone erosions near the joints and systemic bone loss, increasing the risk of fractures. The immune system’s inappropriate activation directly commandeers the bone remodeling machinery, driving it toward destruction.
Certain primary immune deficiencies can manifest with concurrent skeletal defects, showing how problems in the immune cell factory affect the structure it resides in. Alterations in the genes controlling the differentiation of blood cells in the bone marrow can lead to both immunodeficiency and abnormal bone density. These conditions underscore that the skeletal and immune systems operate as an integrated unit, where the dysfunction of one system inevitably impacts the other.