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Review
. 2024 Jul 26;25(15):8163.
doi: 10.3390/ijms25158163.

Balancing the Scales: The Dual Role of Interleukins in Bone Metastatic Microenvironments

Affiliations
Review

Balancing the Scales: The Dual Role of Interleukins in Bone Metastatic Microenvironments

Ahmad Dawalibi et al. Int J Mol Sci. .

Abstract

Bone metastases, a common and debilitating consequence of advanced cancers, involve a complex interplay between malignant cells and the bone microenvironment. Central to this interaction are interleukins (ILs), a group of cytokines with critical roles in immune modulation and inflammation. This review explores the dualistic nature of pro-inflammatory and anti-inflammatory interleukins in bone metastases, emphasizing their molecular mechanisms, pathological impacts, and therapeutic potential. Pro-inflammatory interleukins, such as IL-1, IL-6, and IL-8, have been identified as key drivers in promoting osteoclastogenesis, tumor proliferation, and angiogenesis. These cytokines create a favorable environment for cancer cell survival and bone degradation, contributing to the progression of metastatic lesions. Conversely, anti-inflammatory interleukins, including IL-4, IL-10, and IL-13, exhibit protective roles by modulating immune responses and inhibiting osteoclast activity. Understanding these opposing effects is crucial for developing targeted therapies aimed at disrupting the pathological processes in bone metastases. Key signaling pathways, including NF-κB, JAK/STAT, and MAPK, mediate the actions of these interleukins, influencing tumor cell survival, immune cell recruitment, and bone remodeling. Targeting these pathways presents promising therapeutic avenues. Current treatment strategies, such as the use of denosumab, tocilizumab, and emerging agents like bimekizumab and ANV419, highlight the potential of interleukin-targeted therapies in mitigating bone metastases. However, challenges such as therapeutic resistance, side effects, and long-term efficacy remain significant hurdles. This review also addresses the potential of interleukins as diagnostic and prognostic biomarkers, offering insights into patient stratification and personalized treatment approaches. Interleukins have multifaceted roles that depend on the context, including the environment, cell types, and cellular interactions. Despite substantial progress, gaps in research persist, particularly regarding the precise mechanisms by which interleukins influence the bone metastatic niche and their broader clinical implications. While not exhaustive, this overview underscores the critical roles of interleukins in bone metastases and highlights the need for continued research to fully elucidate their complex interactions and therapeutic potential. Addressing these gaps will be essential for advancing our understanding and treatment of bone metastases in cancer patients.

Keywords: anti-inflammatory; bone metastasis; interleukins; pro-inflammatory; therapy; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Interleukin Regulation of Bone Remodeling. This figure illustrates the complex interactions between interleukins (ILs), immune cells, osteoblasts, and osteoclasts in the bone microenvironment, highlighting the role of these cytokines in the regulation of bone remodeling and formation. Osteoblasts, depicted in blue, produce RANKL (Receptor Activator of Nuclear factor Kappa-Β Ligand), shown as orange circles. RANKL binds to its receptor RANK, expressed on pre-osteoclasts (purple cells) and mature osteoclasts (multinucleated purple cells), promoting osteoclast differentiation and activation, leading to bone resorption. Immune Cells and interleukins: Immune cells (depicted in teal) secrete various interleukins that modulate osteoclastogenesis and osteoblastogenesis. Pro-osteoclastogenic Interleukins: IL-1, IL-6, and IL-17 (indicated by solid arrows) enhance the production of RANKL by osteoblasts and directly promote the differentiation of pre-osteoclasts into mature osteoclasts. Anti-osteoclastogenic Interleukins: IL-4, IL-10, and IL-35 (indicated by red inhibitory lines) inhibit osteoclast differentiation and activity by downregulating RANKL production or directly suppressing pre-osteoclast maturation. It can also simulate osteoblast proliferation.
Figure 2
Figure 2
Interleukin Inhibitors and Denosumab in the Regulation of Osteoclastogenesis in Bone Metastases. This schematic illustrates the role of interleukins (IL) in the regulation of osteoclastogenesis and the therapeutic interventions targeting these pathways to manage bone metastases. Tumor cells in the bone microenvironment secrete IL-8 and IL-11, which stimulate pre-osteoclasts, promoting their differentiation into mature osteoclasts. IL-1 and IL-6 secreted by the tumor cells stimulate osteoblasts to secrete RANKL that bind to the RANK receptors on osteoclast to stimulate their activity. Osteoclasts contribute to bone resorption, which facilitates tumor growth and metastasis. The figure highlights the therapeutic targets and inhibitors involved in this process: canakinumab—An IL-1 inhibitor that blocks the signaling of IL-1, thereby reducing its stimulatory effect on osteoclastogenesis. Siltuximab—An IL-6 inhibitor that blocks IL-6, another cytokine involved in the promotion of osteoclast differentiation and activation. Both inhibitors work by preventing the activation of osteoclasts, thereby mitigating bone resorption and tumor progression. Additionally, the figure depicts the role of Denosumab, a monoclonal antibody that inhibits RANKL (Receptor Activator of Nuclear Factor Kappa-Β Ligand). RANKL is essential for the formation, function, and survival of osteoclasts. By binding to RANKL, Denosumab prevents it from interacting with its receptor RANK on pre-osteoclasts and osteoclasts, thereby inhibiting osteoclastogenesis and reducing bone resorption. This integrative approach of using interleukin inhibitors along with Denosumab offers a promising therapeutic strategy to manage bone metastases by targeting both the cytokine signaling pathways and the direct inhibition of osteoclast formation and activity.

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