A challenge in orthodontic treatment is the long time taken to move teeth, which extends the long treatment period. Accordingly, various treatment protocols and orthodontic materials have been developed to shorten the orthodontic treatment period. However, controlling biological reactions is considered necessary to further shorten this treatment period. Orthodontic force results in compression of the periodontal ligament in the direction of tooth movement, resulting in various reactions in the periodontal ligament that induce osteoclast development, alveolar bone absorption, and teeth movement. The aforementioned reactions include immune reactions. Cytokines are substances responsible for intercellular communication and are involved in various physiological actions, including immune and inflammatory reactions. They cause various cellular responses, including cell proliferation, differentiation, cell death, and functional expression. Various cytokines are involved in biological reactions during orthodontic tooth movement (OTM). It is important to understand the role of cytokines during OTM in order to elucidate their biological response. This review discusses the role of cytokines during OTM.

Osteoclastogenesis—the activation and differentiation of osteoclasts—is one of the pivotal processes of bone remodeling and is regulated by RANKL/RANK signaling, the decoy function of osteoprotegerin (OPG), and a cascade of pro- and anti-inflammatory cytokines. The disruption of this balance leads to pathological bone loss in diseases such as osteoporosis and rheumatoid arthritis. FFAR4 (Free Fatty Acid Receptor 4), a G protein-coupled receptor for long-chain omega-3 fatty acids, has been confirmed as a key mediator of metabolic and anti-inflammatory effects. This review focuses on how FFAR4 acts as the selective receptor for the omega-3 fatty acid docosahexaenoic acid (DHA). It activates two divergent signaling pathways. The Gαq-dependent cascade facilitates intracellular calcium mobilization and ERK1/2 activation. Meanwhile, β-arrestin-2 recruitment inhibits NF-κB. These collective actions reshape the cytokine environment. In macrophages, DHA–FFAR4 signaling lowers the levels of TNF-α, interleukin-6 (IL-6), and IL-1β while increasing IL-10 secretion. Consequently, the activation of NFATc1 and NF-κB p65 is profoundly suppressed under TNF-α or RANKL stimulation. Additionally, DHA modulates the RANKL/OPG axis in osteoblastic cells by suppressing RANKL expression, thereby reducing osteoclast differentiation in an inflammatory mouse model.

Renin–angiotensin–aldosterone system plays a crucial role in the regulation of blood pressure and fluid homeostasis. It is reported to be involved in mediating osteoclastogenesis and bone loss in diseases of inflammatory bone resorption such as osteoporosis. Angiotensin-(1–7), a product of Angiotensin I and II (Ang I, II), is cleaved by Angiotensin-converting enzyme 2 and then binds to Mas receptor to counteract inflammatory effects produced by Ang II. However, the mechanism by which Ang-(1–7) reduces bone resorption remains unclear. Therefore, we aim to elucidate the effects of Ang-(1–7) on lipopolysaccharide (LPS)-induced osteoclastogenesis. In vivo, mice were supracalvarial injected with Ang-(1–7) or LPS ± Ang-(1–7) subcutaneously. Bone resorption and osteoclast formation were compared using micro-computed tomography, tartrate-resistant acid phosphatase (TRAP) stain, and real-time PCR. We found that Ang-(1–7) attenuated tumor necrosis factor (TNF)-α, TRAP, and Cathepsin K expression from calvaria and decreased osteoclast number along with bone resorption at the suture mesenchyme. In vitro, RANKL/TNF-α ± Ang-(1–7) was added to cultures of bone marrow-derived macrophages (BMMs) and osteoclast formation was measured via TRAP staining. The effect of Ang-(1–7) on LPS-induced osteoblasts RANKL expression and peritoneal macrophages TNF-α expression was also investigated. The effect of Ang-(1–7) on the MAPK and NF-κB pathway was studied by Western blotting. As a result, Ang-(1–7) reduced LPS-stimulated macrophages TNF-α expression and inhibited the MAPK and NF-κB pathway activation. However, Ang-(1–7) did not affect osteoclastogenesis induced by RANKL/TNF-α nor reduce osteoblasts RANKL expression in vitro. In conclusion, Ang-(1–7) alleviated LPS-induced osteoclastogenesis and bone resorption in vivo via inhibiting TNF-α expression in macrophages.

Background/Objective: Osteocytes are the most abundant cell type in the skeleton, with key endocrine functions, particularly in regulating osteoblast and osteoclast activity to maintain bone quality. Angiotensin II (Ang II), a critical component of the renin–angiotensin–aldosterone system, is well-known for its role in vasoconstriction during hypertension. Beyond its cardiovascular functions, Ang II participates in various biological processes, including bone metabolism. While its influence on osteoblast proliferation, differentiation, and osteoclastogenesis has been documented, its effects on osteocytes remain unexplored. This study hypothesized that Ang II enhances the osteoclastogenic activity of osteocytes. Methods: Mouse calvariae were cultured ex vivo in an Ang II-containing medium, analyzed via immunohistochemistry, and evaluated for osteoclastogenic gene expression through real-time PCR. Western blotting was employed to assess protein levels and signaling pathway activation in the MLO-Y4 osteocytic cell line in vitro. Results: Ang II significantly increased the expression of receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). These effects were abrogated by azilsartan, a blocker targeting Ang II type 1 receptors (AT1R). p38 and ERK1/2 in the MAPK pathway were also activated by Ang II. Conclusions: Ang II enhances osteocyte-mediated osteoclastogenesis via AT1R activation, highlighting its potential as a therapeutic target for bone diseases.

Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin hormone identified, best known for promoting glucose-stimulated insulin secretion. Increasing evidence has expanded its physiological relevance beyond glucose metabolism, revealing a significant role for GIP in the gut–bone axis. In vitro studies demonstrate that GIP inhibits osteoclast differentiation and activity while promoting osteoblastic bone formation. Findings from genetic animal models and human variant analyses further support the essential role of endogenous GIP signaling in maintaining bone mass and quality. Exogenous administration of GIP suppresses the bone-resorption marker C-terminal telopeptide of type I collagen (CTX) and increases the bone-formation marker procollagen type I N-terminal propeptide (P1NP) in healthy individuals, reflecting an acute shift toward reduced bone resorption and enhanced bone formation. Moreover, GIP confers protection against bone deterioration in multiple pathological conditions, including postmenopausal osteoporosis, inflammatory bone loss, obesity, and diabetes, etc., suggesting therapeutic potential beyond physiological contexts. Recent evidence also shows that GIP attenuates orthodontic tooth movement by limiting mechanically induced osteoclast activity, highlighting its broader skeletal actions. In this review, we summarize recent advances regarding the role of GIP in bone metabolism, integrating evidence from cellular studies, animal models and human investigations, and discuss future directions for GIP-based interventions.

Orthodontic tooth movement (OTM), a complex biological process driven by orchestrated bone remodeling, involves osteoclastic bone resorption and osteoblastic bone formation in response to mechanical force. Traditionally, OTM-related cell death has been discussed in terms of apoptosis and necrosis. However, recent advances in cell death research have revealed various forms of regulated cell death (RCD) beyond these conventional categories. This review summarizes the current understanding of the diverse RCD pathways and their roles in various cell populations during OTM. It delineates the involvement of distinct RCD mechanisms, including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis. On the compression side, these RCD pathways in periodontal ligament (PDL) cells, cementoblasts, cementocytes, and bone-related cells actively drive inflammatory responses, promote bone resorption, and contribute to root resorption. Conversely, on the tension side, specific RCD pathways, notably autophagy in the PDL and osteocytes, play crucial roles in promoting osteogenesis and tissue repair. Collectively, cell death is not merely a passive elimination of cells but actively functions as a critical switch for alveolar bone remodeling during OTM. Understanding these multifaceted RCD mechanisms provides novel insights into the biological regulation of tooth movement and identifies potential therapeutic targets for enhancing tooth movement efficiency and mitigating adverse effects.