In this second installment of our blog series on Osteoimmunology, we’ll explore the intricate connection between immunity and bone health, and how this interplay influences repair processes.
The Immune System: A Dual Defense Mechanism
The immune system functions to protect the body against foreign invaders (antigens), including bacteria, viruses, and toxins. It also plays a role in directing tissue repair, including bone healing after injuries. The immune system mediates its defense through two complementary mechanisms.

  1. Innate immunity: the first line of defense, acting immediately after injury or antigen exposure. It’s nonspecific and antigen-independent, providing rapid protection.  

  2. Adaptive immunity: The second line of defense, marked by the generation of antibodies (B-cells) and cytokines (T-cells). It’s antigen-specific and requires time to mount a response, but it creates immunologic memory for faster reactions in the future.  

Together, these systems work to defend against pathogens and facilitate tissue repair. Any defects in either system can lead to increased vulnerability to disease or impaired healing (1).
The RANK/RANKL/OPG Axis: A Balancing Act in Bone Repair

The RANK/RANKL/OPG complex is a critical pathway linking immune and skeletal systems. It regulates bone remodeling and repair by balancing bone resorption and formation (2):

  • RANK (Receptor Activator of Nuclear Factor Kappa-B): a receptor on the osteoclast precursors that promotes their differentiation and activation for bone resorption

  • RANKL (RANK Ligand): Produced by osteoblasts, osteocytes, and stromal cells, it binds to RANK to stimulate osteoclast activity, ensuring damaged bone is cleared during repair.

  • OPG (Osteoprotegerin): A decoy receptor secreted by osteoblasts and stromal cells, it binds to RANKL to inhibit osteoclast activation, limiting bone resorption.

This delicate balance is essential for effective bone repair. Dysregulation can lead to conditions like osteoporosis or delayed fracture healing.
Innate Immunity: The First Responder in Bone Repair
When you break a bone, your innate immune system springs into action. Within minutes, immune cells such as neutrophils and monocytes race to the injury site, initiating acute inflammation (3). Here’s how they contribute to bone repair:

  1. Neutrophils: Express high levels of RANKL, promoting osteoclastic bone resorption.

  2. Monocytes: Differentiate into macrophages which:

    1. Drive the inflammation occurring at the injury site during the initial phase of healing.

    2. Resolve inflammation and coordinate tissue regeneration in later stages.

    3. Present antigens to T cells and secrete inflammatory mediators to recruit other immune cells. 

  3. Dendritic Cells: Trigger the cytotoxic T cell response during the initial inflammation phase (4,5).

Any disruption in these processes can result in complications like non-union or delayed union of fractures.
Adaptive Immunity: The Regulator of Bone Health
After the innate immune system sets the stage, adaptive immunity takes over to regulate the bone repair process. T lymphocytes play a central role (2):

  1. T-helper (Th) Cells:

    1. Th1 Cells: Activate macrophages and eliminate intracellular pathogens through cytokines like IL-12 and TNF-α.

    2. Th2 Cells: Facilitate the removal of extracellular microorganisms and stimulate B cells, granulocytes, and mast cells.

  2. B lymphocytes: Present antigens to activate T cells and secrete cytokines like RANKL, contributing to osteoclastogenesis.

  3. Dendritic cells: Produce OPG to limit osteoclast activity during the later stages of bone repair (5).

  4. Macrophages: Transition from pro-inflammatory to anti-inflammatory states, secreting growth factors like TGF-β and VEGF, which promote tissue regeneration and angiogenesis. They also release BMP-2 to stimulate osteoblast activity.

Immunity and Bone Health: It’s A Delicate Balance

Understanding the crosstalk between bones and the immune system is key to maintaining bone health, augmenting bone repair, and developing novel treatments for inflammatory bone diseases. Curious to learn more? Explore our blog series to see how science and innovation are shaping the future of bone health.

References:

  1. Marshall, J. S., Warrington, R., Watson, W., & Kim, H. L. (2018). An introduction to immunology and immunopathology. Allergy, Asthma & Clinical Immunology, 14(S2), 49. https://doi.org/10.1186/s13223-018-0278-1

  2. Udagawa, N., Koide, M., Nakamura, M. et al. Osteoclast differentiation by RANKL and OPG signaling pathways. J Bone Miner Metab 39, 19–26 (2021). https://doi.org/10.1007/s00774-020-01162-6

  3. Bergin, S. M., Crutcher, C. L., Keeler, C., Rocos, B., Haglund, M. M., Michael Guo, H., Gottfried, O. N., Richardson, W. J., & Than, K. D. (2023). Osteoimmunology: Interactions With the Immune System in Spinal Fusion. International Journal of Spine Surgery, 17(S3), S9–S17. https://doi.org/10.14444/8556

  4. Fischer, V., & Haffner-Luntzer, M. (2022). Interaction between bone and immune cells: Implications for postmenopausal osteoporosis. Seminars in Cell & Developmental Biology, 123, 14–21. https://doi.org/10.1016/j.semcdb.2021.05.014

  5. Molitoris, K. H., Huang, M., & Baht, G. S. (2024). Osteoimmunology of Fracture Healing. Current Osteoporosis Reports. https://doi.org/10.1007/s11914-024-00869-z

  6. Lévesque JP, Helwani FM, Winkler IG. The endosteal ‘osteoblastic’ niche and its role in hematopoietic stem cell homing and mobilization. Leukemia. 2010 Dec;24(12):1979-92. doi: 10.1038/leu.2010.214. Epub 2010 Sep 23. PMID: 20861913.

  7. Hurwitz SN, Jung SK, Kurre P. Hematopoietic stem and progenitor cell signaling in the niche. Leukemia. 2020 Dec;34(12):3136-3148. doi: 10.1038/s41375-020-01062-8. Epub 2020 Oct 19. PMID: 33077865.

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