(648c) Computational Modeling of the Relationship between Immune Cell Populations and the Bone Remodeling Cycle

Bone health is determined by many factors including the remodeling cycle. At any time, many sections of bone are going through a remodeling cycle. Depending on different signaling factors, the cycle will end with the same amount of bone as at the beginning of the remodeling cycle (healthy) or increased or decreased amounts of bone (these changes contribute to chronic bone diseases). A decrease in bone density is commonly referred to as osteoporosis. Osteoporosis can be caused by several different disruptions of the remodeling process. Recently immune cells have been identified as major signaling factors for this process. However, it is unclear how and to what extent they affect bone homeostasis.

In this study we focused primarily on the different immune cell populations (primarily various T cells) and their interactions with the bone remodeling process. T cells have been shown to regulate bone remodeling through the secretion of different cytokines and proteins. Depending on their population type and activation, T cells stimulate either bone formation or resorption. Tregs have been shown to activate CD8⁺ T cells causing them to secrete Wnt-10b, a positive regulator of bone formation (Tyagi et al., 2018). When activated by an immune response, Tregs secrete DKK1, which inhibits the Wnt mediated bone formation pathway (Lehmann et al., 2021). CD4⁺ T cells differentiate into Th17 cells when activated by TGF-β and IL-6. These Th17 cells secrete a number of bone resorption cytokines and proteins including IL-6, RANKL and TNF-α (Srivastava, Dar, & Mishra, 2018). Clearly the interactions between bone and T cells are numerous and complex.

To better understand the relationship between T cells and bone remodeling, we developed a computational model that tracks how some of these T cell populations and their products such as Wnt10b affect bone health. More specifically we have connected the disturbances caused by T cells of interest to a model of bone remodeling that predicts if bone density will increase or decrease through osteoblasts (bone forming cells) and osteoclast (bone resorbing cells) populations.

This model improves the understanding of immune cell disturbances to bone homeostasis and can help identify targets for medical intervention of bone loss since T cells play an important role in osteoporosis caused by rheumatoid arthritis, estrogen deficiency, and general aging (Zhang, Dang, Huai, & Qian, 2020).

References:

Lehmann, J., Thiele, S., Baschant, U., Rachner, T. D., Niehrs, C., Hofbauer, L. C., & Rauner, M. (2021). Mice lacking DKK1 in T cells exhibit high bone mass and are protected from estrogen deficiency-induced bone loss. iScience, 102224. doi:10.1016/j.isci.2021.102224

Srivastava, R. K., Dar, H. Y., & Mishra, P. K. (2018). Immunoporosis: Immunology of Osteoporosis-Role of T Cells. Front Immunol, 9, 657. doi:10.3389/fimmu.2018.00657

Tyagi, A. M., Yu, M., Darby, T. M., Vaccaro, C., Li, J. Y., Owens, J. A., . . . Pacifici, R. (2018). The Microbial Metabolite Butyrate Stimulates Bone Formation via T Regulatory Cell-Mediated Regulation of WNT10B Expression. Immunity, 49(6), 1116-1131 e1117. doi:10.1016/j.immuni.2018.10.013

Zhang, W., Dang, K., Huai, Y., & Qian, A. (2020). Osteoimmunology: The Regulatory Roles of T Lymphocytes in Osteoporosis. Front Endocrinol (Lausanne), 11, 465. doi:10.3389/fendo.2020.00465

Acknowledgment: This work was supported by the National Institutes of Health grant R35GM133763 and the University at Buffalo.