Rheumatology: Current Research
Open Access

Modulation of Bone Remodeling and Inflammation of Osteoblast-Immune Cell Crosstalk

Yang Yerin^{* *}Correspondence: Yang Yerin, Department of Orthopedics, Zhejiang University, Zhejiang, China, Email:

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About the Study

Bone is a dynamic tissue characterized by continuous remodeling, a tightly regulated process involving bone formation by osteoblasts and resorption by osteoclasts. This remodeling is essential for maintaining skeletal integrity, repairing microdamage, and responding to mechanical and metabolic demands. Emerging evidence suggests that the immune system intricately regulates bone remodeling through bidirectional communication with bone cells, particularly osteoblasts. Osteoblasts, traditionally known for their role in bone formation, also exhibit immune-regulatory functions, while immune cells influence bone remodeling through the secretion of cytokines, chemokines, and other signaling molecules.

The crosstalk between osteoblasts and immune cells occurs in various physiological and pathological conditions, modulating both bone remodeling and inflammation.

Osteoblast-immune cell crosstalk in bone remodeling

Osteoblasts, derived from mesenchymal stem cells, are responsible for synthesizing and mineralizing the bone matrix during bone formation. Apart from their canonical role in osteogenesis, osteoblasts also participate in immune regulation by expressing various immune-related molecules such as cytokines, chemokines, and cell surface receptors. Conversely, immune cells, including macrophages, T cells, and B cells, influence bone remodeling through the secretion of cytokines and direct interactions with osteoblasts.

One of the central mediators of osteoblast-immune cell crosstalk is the Receptor Activator of Nuclear factor Kappa-B ligand (RANKL) and its decoy receptor Osteoprotegerin (OPG). Osteoblasts express RANKL, which interacts with its receptor RANK on osteoclast precursors, promoting osteoclast differentiation and activation. OPG, produced by osteoblasts, acts as a decoy receptor for RANKL, thereby inhibiting osteoclastogenesis and bone resorption. Immune cells, particularly T cells, can also produce RANKL, contributing to osteoclast activation and bone loss in inflammatory conditions.

Moreover, osteoblasts secrete various cytokines and chemokines that regulate immune cell recruitment and function within the bone microenvironment. For instance, Interleukin-6 (IL-6) produced by osteoblasts promotes osteoclast differentiation and activation while also modulating immune cell responses. Additionally, osteoblast-derived chemokines such as CCL2 (Chemokine Ligand 2) and CXCL12 (Chemokine Ligand 12) regulate the migration and homing of immune cells to bone tissues, further shaping the local immune response and bone remodeling.

Conversely, immune cells play a crucial role in regulating osteoblast function and bone formation. Macrophages, in particular, exhibit plasticity and can adopt distinct phenotypes depending on the microenvironment. M1 macrophages, activated by pro-inflammatory stimuli such as Lipopolysaccharide (LPS) and Interferon-Gamma (IFN-γ), promote inflammation and inhibit osteoblast differentiation and activity. In contrast, M2 macrophages, induced by anti-inflammatory signals such as Interleukin-4 (IL-4) and Interleukin-13 (IL-13), support tissue repair and enhance osteoblast function.

Furthermore, T cells, especially T helper 17 (Th17) cells, produce pro-inflammatory cytokines such as Interleukin-17 (IL-17) and Interleukin-22 (IL-22), which can directly or indirectly inhibit osteoblast differentiation and function. Regulatory T cells (Tregs), on the other hand, exert immunosuppressive effects and promote osteoblast activity through the secretion of antiinflammatory cytokines like Interleukin-10 (IL-10) and Transforming Growth Factor-beta (TGF-β).

Implications for bone health and disease

The dynamic interplay between osteoblasts and immune cells is critical for maintaining bone homeostasis. However, dysregulation of this crosstalk can lead to pathological conditions characterized by altered bone remodeling and inflammation. Osteoporosis, a common skeletal disorder characterized by low bone mass and increased fracture risk, is associated with imbalances in osteoblast and osteoclast activity.

In postmenopausal osteoporosis, estrogen deficiency leads to increased production of pro-inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-1 (IL-1), which promote osteoclastogenesis and bone resorption. Additionally, dysregulation of immune cell populations, such as an imbalance between Th17 cells and Tregs, contributes to enhanced bone loss and impaired bone formation in osteoporotic individuals.

Inflammatory bone diseases, such as Rheumatoid Arthritis (RA) and periodontitis, are characterized by chronic inflammation within the bone microenvironment, leading to progressive bone destruction. In RA, pro-inflammatory cytokines produced by immune cells, including TNF-α and IL-6, stimulate osteoclastogenesis and inhibit osteoblast function, resulting in joint erosion and bone loss. Similarly, in periodontitis, the dysregulated immune response to bacterial pathogens leads to inflammation-induced bone resorption mediated by osteoclast activation.

Moreover, immune-mediated bone loss can occur in conditions such as glucocorticoid-induced osteoporosis, where prolonged exposure to glucocorticoid hormones suppresses osteoblast activity and enhances osteoclastogenesis, resulting in bone fragility. Understanding the underlying mechanisms of osteoblast-immune cell crosstalk in these diseases is essential for developing targeted therapeutic interventions.

Therapeutic strategies targeting osteoblast-immune cell interactions

Given the pivotal role of osteoblast-immune cell crosstalk in bone remodeling and inflammation, targeting this interaction holds promise for the treatment of skeletal disorders. Several therapeutic strategies have been proposed to modulate osteoblast and immune cell function, aiming to restore bone homeostasis and mitigate inflammation-associated bone loss.

Anti-cytokine therapy: Biologic agents targeting proinflammatory cytokines such as TNF-α and IL-6 have shown efficacy in reducing inflammation and bone loss in conditions like RA and glucocorticoid-induced osteoporosis. By inhibiting these cytokines, these therapies suppress osteoclast activation and promote osteoblast function, thereby preserving bone density and integrity.

Osteoanabolic agents: Anabolic agents such as Parathyroid Hormone (PTH) analogs and sclerostin inhibitors stimulate osteoblast activity and bone formation, offering potential treatments for osteoporosis and other bone disorders characterized by impaired bone formation. By enhancing osteoblast function, these agents counteract the effects of inflammation and promote bone repair and regeneration.

Immunomodulatory drugs: Drugs targeting immune cell populations, such as T cell modulators and monoclonal antibodies against immune checkpoints, have been explored for their potential to regulate immune responses and restore bone homeostasis. By modulating the balance between proinflammatory and anti-inflammatory immune cells, these drugs may attenuate inflammation-induced bone loss and promote bone healing.

Cellular therapy: Emerging approaches utilizing Mesenchymal Stem Cell (MSC) therapy aim to harness the immunomodulatory properties of MSCs to regulate immune responses and promote tissue repair, including bone regeneration. MSCs can modulate the activity of immune cells and promote osteoblast differentiation, offering potential therapeutic benefits for inflammatory bone diseases and osteoporosis.

Osteoblast-immune cell crosstalk plays a crucial role in regulating bone remodeling and inflammation, influencing skeletal integrity and immune responses. The intricate signaling pathways and molecular interactions between osteoblasts and immune cells shape the bone microenvironment, maintaining bone homeostasis under physiological conditions and contributing to skeletal pathology when dysregulated.