Inflammatory bone loss and signaling pathways in periodontitis: mechanistic insights and emerging therapeutic strategies

Abstract

Bone resorption is a vital physiological process that enables skeletal remodeling, maintenance, and adaptation to mechanical forces throughout life. While tightly regulated under the physiological state, its dysregulation contributes to pathological conditions such as osteoporosis, rheumatoid arthritis, and periodontitis. Periodontitis is a highly prevalent chronic inflammatory disease driven by dysbiotic biofilms that disrupt the oral microbiome, leading to the progressive breakdown of the periodontal ligament, cementum, and alveolar bone and ultimately resulting in tooth loss. This review outlines the molecular and cellular mechanisms underlying periodontitis, focusing on osteoclastogenesis, the differentiation and activation of osteoclasts, the primary mediators of bone resorption. Key transcriptional regulators, including NFATc1, c-Fos, and c-Src are discussed alongside major signaling pathways such as Mitogen Activated Protein Kinase (MAPK), Janus Tyrosine Kinase/Signal Transducer and Activator of Transcription (JAK/STAT), Nuclear Factor Kappa B (NF-κB), and Phosphoinositide 3-kinase (PI3K)/Akt, to elucidate their roles in the initiation and progression of periodontal bone loss. These pathways orchestrate the inflammatory response and osteoclast activity, underscoring their relevance in periodontitis and other osteolytic conditions. Hallmark features of periodontitis, including chronic inflammation, immune dysregulation, and tissue destruction are highlighted, with emphasis on current and emerging therapeutic strategies targeting these molecular pathways. Special attention is given to small molecules, biologics, and natural compounds that have the potential to modulate key signaling pathways. Although advances in understanding these mechanisms have identified promising therapeutic targets, translation into effective clinical interventions remains challenging. Continued research into regulating bone-resorptive signaling pathways is essential for developing more effective treatments for periodontitis and related inflammatory bone diseases.

References

[1] Hienz SA, Paliwal S, Ivanovski S. Mechanisms of bone resorption in periodontitis. J. Immunol. Res., 2015, 2015 615486

[2] de Molon RS, de Avila ED, Cirelli JA, Steffens JP. Periodontal research contributions to basic sciences: from cell communication and host-parasite interactions to inflammation and bone biology. Biocell, 2022, 46: 633-638

[3] Caton JG, et al.. A new classification scheme for periodontal and peri-implant diseases and conditions—introduction and key changes from the 1999 classification. J. Clin. Periodontol., 2018, 45: S1-S8

[4] Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat. Rev. Immunol., 2015, 15: 30-44

[5] Hajishengallis G, Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat. Rev. Immunol., 2021, 21: 426-440

[6] Kinane, D. F., Lappin, D. F. & Culshaw, S. The role of acquired host immunity in periodontal diseases. Periodontolhttps://doi.org/10.1111/prd.12562 (2024).

[7] Pan W, Wang Q, Chen Q. The cytokine network involved in the host immune response to periodontitis. Int. J. Oral. Sci., 2019, 11: 30

[8] Eke PI, Thornton-Evans G, Dye B, Genco R. Advances in surveillance of periodontitis: the centers for disease control and prevention periodontal disease surveillance project. J. Periodontol., 2012, 83: 1337-1342

[9] Kassebaum NJ, et al.. Global burden of severe periodontitis in 1990-2010: a systematic review and meta-regression. J. Dent. Res, 2014, 93: 1045-1053

[10] Eke PI, et al.. Update on prevalence of periodontitis in adults in the United States: NHANES 2009 to 2012. J. Periodontol., 2015, 86: 611-622

[11] Balta MG, Papathanasiou E, Blix IJ, Van Dyke TE. Host modulation and treatment of periodontal disease. J. Dent. Res., 2021, 100: 798-809

[12] Phipps KR, Stevens VJ. Relative contribution of caries and periodontal disease in adult tooth loss for an HMO dental population. J. Public Health Dent., 1995, 55: 250-252

[13] Listl S, Galloway J, Mossey PA, Marcenes W. Global economic impact of dental diseases. J. Dent. Res., 2015, 94: 1355-1361

[14] de Aquino SG, et al.. Periodontal pathogens directly promote autoimmune experimental arthritis by inducing a TLR2- and IL-1-driven Th17 response. J. Immunol., 2014, 192: 4103-4111

[15] de Molon RS, Rossa C, Thurlings RM, Cirelli JA, Koenders MI. Linkage of periodontitis and rheumatoid arthritis: current evidence and potential biological interactions. Int. J. Mol. Sci, 2019, 20: 4541

[16] de Aquino SG, et al.. The aggravation of arthritis by periodontitis is dependent of IL-17 receptor A activation. J. Clin. Periodontol., 2017, 44: 881-891

[17] Gonzalez-Febles J, Sanz M. Periodontitis and rheumatoid arthritis: what have we learned about their connection and their treatment?. Periodontol 2000, 2021, 87: 181-203

[18] Shahbaz M, et al.. Connecting the dots: NETosis and the periodontitis-rheumatoid arthritis nexus. Int. J. Rheum. Dis., 2024, 27 e15415

[19] Belizario, L. C. G. et al. The impact of type 2 diabetes mellitus on non-surgical periodontal treatment: a non-randomized clinical trial. J. Clin. Med.13, 5978 (2024).

[20] de Molon, R. S. et al. The efficacy of topical or systemic antibiotics as adjuvants to non-surgical periodontal treatment in diabetic patients: a systematic review and meta-analysis of randomized clinical trials. J. Clin. Med.13, 4763 (2024).

[21] Lalla E, Papapanou PN. Diabetes mellitus and periodontitis: a tale of two common interrelated diseases. Nat. Rev. Endocrinol., 2011, 7: 738-748

[22] Wu CZ, et al.. Epidemiologic relationship between periodontitis and type 2 diabetes mellitus. BMC Oral. Health, 2020, 20 204

[23] Rodrigues, J. V. S. et al. The effect of non-surgical periodontal treatment on patients with combined refractory arterial hypertension and stage III, Grade B periodontitis: a preliminary prospective clinical study. J. Clin. Med.12, 4277 (2023).

[24] Rosa, R. A. C. et al. The relationship between hypertension and periodontitis: a cross-sectional study. J. Clin. Med.12, 5140 (2023).

[25] Khumaedi AI, Purnamasari D, Wijaya IP, Soeroso Y. The relationship of diabetes, periodontitis and cardiovascular disease. Diab. Metab. Syndr., 2019, 13: 1675-1678

[26] Liccardo, D. et al. Periodontal disease: a risk factor for diabetes and cardiovascular disease. Int. J. Mol. Sci. 20, 1414 (2019).

[27] Sanz M, et al.. Periodontitis and cardiovascular diseases: consensus report. J. Clin. Periodontol., 2020, 47: 268-288

[28] Chapple ILC, Hirschfeld J, Cockwell P, Dietrich T, Sharma P. Interplay between periodontitis and chronic kidney disease. Nat. Rev. Nephrol., 2025, 21: 226-240

[29] Kuraji R, Sekino S, Kapila Y, Numabe Y. Periodontal disease-related nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: an emerging concept of oral-liver axis. Periodontol 2000, 2021, 87: 204-240

[30] Baima G, et al.. Periodontitis and risk of cancer: mechanistic evidence. Periodontol 2000, 2024, 96: 83-94

[31] Zhou Y, Meyle J, Groeger S. Periodontal pathogens and cancer development. Periodontol 2000, 2024, 96: 112-149

[32] Beck JD, Papapanou PN, Philips KH, Offenbacher S. Periodontal medicine: 100 years of progress. J. Dent. Res., 2019, 98: 1053-1062

[33] Theodoro LH, et al.. Role of junctional epithelium in maintaining dento-gingival adhesion and periodontal health. Front. Dent. Med., 2023, 4 1144537

[34] Gomes, N. A. et al. Expression and localization of amelotin, laminin, and protein secreted by follicular dendritic cells after ligature-induced experimental periodontitis in rats. Br. Dent. J.https://doi.org/10.1038/s41415-025-8508-7. (2025).

[35] Hajishengallis G, Chavakis T, Lambris JD. Current understanding of periodontal disease pathogenesis and targets for host-modulation therapy. Periodontol 2000, 2020, 84: 14-34

[36] Abdulkareem AA, et al.. Current concepts in the pathogenesis of periodontitis: from symbiosis to dysbiosis. J. Oral. Microbiol., 2023, 15 2197779

[37] Kirkwood KL, Cirelli JA, Rogers JE, Giannobile WV. Novel host response therapeutic approaches to treat periodontal diseases. Periodontol 2000, 2007, 43: 294-315

[38] Kirkwood KL, Rossa CJr. The potential of p38 MAPK inhibitors to modulate periodontal infections. Curr. Drug Metab., 2009, 10: 55-67

[39] Souza JA, Rossa CJr, Garlet GP, Nogueira AV, Cirelli JA. Modulation of host cell signaling pathways as a therapeutic approach in periodontal disease. J. Appl. Oral. Sci., 2012, 20: 128-138

[40] Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch. Biochem. Biophys., 2008, 473: 139-146

[41] De Leon-Oliva D, et al.. The RANK-RANKL-OPG system: a multifaceted regulator of homeostasis, immunity, and cancer. Medicina, 2023, 59: 1752

[42] Di Cicco G, et al.. The pathogenetic role of RANK/RANKL/OPG signaling in osteoarthritis and related targeted therapies. Biomedicines, 2024, 12: 2292

[43] Silva N, et al.. Host response mechanisms in periodontal diseases. J. Appl. Oral. Sci., 2015, 23: 329-355

[44] Hajishengallis G. Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response. Trends Immunol., 2014, 35: 3-11

[45] Jakubovics NS, Goodman SD, Mashburn-Warren L, Stafford GP, Cieplik F. The dental plaque biofilm matrix. Periodontol 2000, 2021, 86: 32-56

[46] Graves DT, Li J, Cochran DL. Inflammation and uncoupling as mechanisms of periodontal bone loss. J. Dent. Res., 2011, 90: 143-153

[47] Isola G, et al.. Periodontal health and disease in the context of systemic diseases. Mediators Inflamm., 2023, 2023 9720947

[48] Sirisereephap, K. et al. Osteoimmunology in periodontitis: local proteins and compounds to alleviate periodontitis. Int. J. Mol. Sci.23, 5540 (2022).

[49] Valverde A, George A, Nares S, Naqvi AR. Emerging therapeutic strategies targeting bone signaling pathways in periodontitis. J. Periodontal Res., 2025, 60: 101-120

[50] Usui M, et al.. Mechanism of alveolar bone destruction in periodontitis—periodontal bacteria and inflammation. Jpn Dent. Sci. Rev., 2021, 57: 201-208

[51] Hajishengallis G, Darveau RP, Curtis MA. The keystone-pathogen hypothesis. Nat. Rev. Microbiol., 2012, 10: 717-725

[52] Kinane DF, Lappin DF. Immune processes in periodontal disease: a review. Ann. Periodontol., 2002, 7: 62-71

[53] He H, Hao Y, Fan Y, Li B, Cheng L. The interaction between innate immunity and oral microbiota in oral diseases. Expert Rev. Clin. Immunol., 2023, 19: 405-415

[54] Hajishengallis G, Diaz PI. Porphyromonas gingivalis: immune subversion activities and role in periodontal dysbiosis. Curr. Oral. Health Rep., 2020, 7: 12-21

[55] Cekici A, Kantarci A, Hasturk H, Van Dyke TE. Inflammatory and immune pathways in the pathogenesis of periodontal disease. Periodontol 2000, 2014, 64: 57-80

[56] Gu, Y. & Han, X. Toll-like receptor signaling and immune regulatory lymphocytes in periodontal disease. Int. J. Mol. Sci.21, 3329 (2020).

[57] Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol., 2018, 18: 134-147

[58] Castanheira FVS, Kubes P. Neutrophils and NETs in modulating acute and chronic inflammation. Blood, 2019, 133: 2178-2185

[59] Mousa AO, Al Hussaini AHA, Hussein HM. The potential role of reactive oxygen species produced by low-density neutrophils in periodontitis. Eur. J. Dent., 2024, 18: 1142-1148

[60] Gysemans, C., Beya, M., Pedace, E. & Mathieu, C. Exploring neutrophil heterogeneity and plasticity in health and disease. Biomedicines13, 597 (2025).

[61] Moutsopoulos NM, Konkel JE. Tissue-specific immunity at the oral mucosal barrier. Trends Immunol., 2018, 39: 276-287

[62] Kantarci A, Oyaizu K, Van Dyke TE. Neutrophil-mediated tissue injury in periodontal disease pathogenesis: findings from localized aggressive periodontitis. J. Periodontol., 2003, 74: 66-75

[63] Dutzan, N. et al. A dysbiotic microbiome triggers T(H)17 cells to mediate oral mucosal immunopathology in mice and humans. Sci. Transl. Med.10, eaat0797 (2018).

[64] Hajishengallis G, Lamont RJ. Breaking bad: manipulation of the host response by Porphyromonas gingivalis. Eur. J. Immunol., 2014, 44: 328-338

[65] Chapple, I. L. C., Hirschfeld, J., Kantarci, A., Wilensky, A. & Shapira, L. The role of the host-Neutrophil biology. Periodontol2000. https://doi.org/10.1111/prd.12490 (2023).

[66] Konig MF, Andrade F. A critical reappraisal of neutrophil extracellular traps and NETosis mimics based on differential requirements for protein citrullination. Front Immunol., 2016, 7: 461

[67] White PC, Chicca IJ, Cooper PR, Milward MR, Chapple IL. Neutrophil extracellular traps in periodontitis: a web of intrigue. J. Dent. Res., 2016, 95: 26-34

[68] Divangahi M, et al.. Trained immunity, tolerance, priming and differentiation: distinct immunological processes. Nat. Immunol., 2021, 22: 2-6

[69] Li X, et al.. Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities. Cell, 2022, 185: 1709-1727.e1718

[70] Haacke N, et al.. Innate immune training of osteoclastogenesis promotes inflammatory bone loss in mice. Dev. Cell, 2025, 60: 1854-1870

[71] Mo K, Wang Y, Lu C, Li Z. Insight into the role of macrophages in periodontitis restoration and development. Virulence, 2024, 15 2427234

[72] Sun X, et al.. Polarized macrophages in periodontitis: characteristics, function, and molecular signaling. Front. Immunol., 2021, 12 763334

[73] Kini V, Mohanty I, Telang G, Vyas N. Immunopathogenesis and distinct role of Th17 in periodontitis: a review. J. Oral. Biosci., 2022, 64: 193-201

[74] Bunte K, Beikler T. Th17 Cells and the IL-23/IL-17 axis in the pathogenesis of periodontitis and immune-mediated inflammatory diseases. Int. J. Mol. Sci., 2019, 20: 3394

[75] Gaffen SL, Hajishengallis G. A new inflammatory cytokine on the block: re-thinking periodontal disease and the Th1/Th2 paradigm in the context of Th17 cells and IL-17. J. Dent. Res., 2008, 87: 817-828

[76] Rastogi I, et al.. Role of B cells as antigen presenting cells. Front. Immunol., 2022, 13 954936

[77] de Gruijter NM, Jebson B, Rosser EC. Cytokine production by human B cells: role in health and autoimmune disease. Clin. Exp. Immunol., 2022, 210: 253-262

[78] Huang J, Cai X, Ou Y, Zhou Y, Wang Y. Resolution of inflammation in periodontitis: a review. Int. J. Clin. Exp. Pathol., 2018, 11: 4283-4295

[79] Van Dyke TE, Sima C. Understanding resolution of inflammation in periodontal diseases: Is chronic inflammatory periodontitis a failure to resolve?. Periodontol 2000, 2020, 82: 205-213

[80] Eltay EG, Van Dyke T. Resolution of inflammation in oral diseases. Pharm. Ther., 2023, 247 108453

[81] Mizraji G, Heyman O, Van Dyke TE, Wilensky A. Resolvin D2 restrains Th1 immunity and prevents alveolar bone loss in murine periodontitis. Front. Immunol., 2018, 9: 785

[82] Sahni V, Van Dyke TE. Immunomodulation of periodontitis with SPMs. Front. Oral. Health, 2023, 4 1288722

[83] Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature, 2014, 510: 92-101

[84] Van Dyke TE. Pro-resolving mediators in the regulation of periodontal disease. Mol. Asp. Med., 2017, 58: 21-36

[85] Freire MO, Van Dyke TE. Natural resolution of inflammation. Periodontol 2000, 2013, 63: 149-164

[86] Huang N, Gibson FC. 3rd. Immuno-pathogenesis of periodontal disease: current and emerging paradigms. Curr. Oral. Health Rep., 2014, 1: 124-132

[87] Sima C, Glogauer M. Macrophage subsets and osteoimmunology: tuning of the immunological recognition and effector systems that maintain alveolar bone. Periodontol 2000, 2013, 63: 80-101

[88] Hathaway-Schrader JD, Novince CM. Maintaining homeostatic control of periodontal bone tissue. Periodontol 2000, 2021, 86: 157-187

[89] Zhang M, Liu Y, Afzali H, Graves DT. An update on periodontal inflammation and bone loss. Front. Immunol., 2024, 15 1385436

[90] Ferrara E, Mastrocola F. Pattern recognition receptors in periodontal disease: molecular mechanisms, signaling pathways, and therapeutic implications. J. Mol. Pathol., 2024, 5: 497-511

[91] Seeman E. Bone modeling and remodeling. Crit. Rev. Eukaryot. Gene Expr., 2009, 19: 219-233

[92] Iniguez-Ariza NM, Clarke BL. Bone biology, signaling pathways, and therapeutic targets for osteoporosis. Maturitas, 2015, 82: 245-255

[93] Bolamperti S, Villa I, Rubinacci A. Bone remodeling: an operational process ensuring survival and bone mechanical competence. Bone Res., 2022, 10: 48

[94] Sabokbar A, Mahoney DJ, Hemingway F, Athanasou NA. Non-canonical (RANKL-independent) pathways of osteoclast differentiation and their role in musculoskeletal diseases. Clin. Rev. Allergy Immunol., 2016, 51: 16-26

[95] Sromova V, Sobola D, Kaspar P. A brief review of bone cell function and importance. Cells, 2023, 12: 2576

[96] Daponte V, Henke K, Drissi H. Current perspectives on the multiple roles of osteoclasts: mechanisms of osteoclast-osteoblast communication and potential clinical implications. Elife, 2024, 13: e95083

[97] Kim JM, Lin C, Stavre Z, Greenblatt MB, Shim JH. Osteoblast-osteoclast communication and bone homeostasis. Cells, 2020, 9: 2073

[98] Hascoet E, et al.. New insights into inflammatory osteoclast precursors as therapeutic targets for rheumatoid arthritis and periodontitis. Bone Res., 2023, 11: 26

[99] Xu H, et al.. Targeting strategies for bone diseases: signaling pathways and clinical studies. Signal Transduct. Target Ther., 2023, 8: 202

[100] Feng X, Teitelbaum SL. Osteoclasts: new insights. Bone Res., 2013, 1: 11-26

[101] Veis DJ, O’Brien CA. Osteoclasts, master sculptors of bone. Annu. Rev. Pathol., 2023, 18: 257-281

[102] Grewe JM, et al.. The role of sphingosine-1-phosphate in bone remodeling and osteoporosis. Bone Res., 2022, 10: 34

[103] Soe K, Delaisse JM, Borggaard XG. Osteoclast formation at the bone marrow/bone surface interface: importance of structural elements, matrix, and intercellular communication. Semin. Cell Dev. Biol., 2021, 112: 8-15

[104] Ishii M, et al.. Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature, 2009, 458: 524-528

[105] Theill LE, Boyle WJ, Penninger JM. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu. Rev. Immunol., 2002, 20: 795-823

[106] Xiong J, et al.. Matrix-embedded cells control osteoclast formation. Nat. Med., 2011, 17: 1235-1241

[107] Asagiri M, et al.. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J. Exp. Med., 2005, 202: 1261-1269

[108] Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature, 2003, 423: 337-342

[109] Takayanagi H, et al.. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell, 2002, 3: 889-901

[110] Vaananen HK, Horton M. The osteoclast clear zone is a specialized cell-extracellular matrix adhesion structure. J. Cell Sci., 1995, 108: 2729-2732

[111] Nesbitt SA, Horton MA. Trafficking of matrix collagens through bone-resorbing osteoclasts. Science, 1997, 276: 266-269

[112] Takegahara N, Kim H, Choi Y. Unraveling the intricacies of osteoclast differentiation and maturation: insight into novel therapeutic strategies for bone-destructive diseases. Exp. Mol. Med., 2024, 56: 264-272

[113] Vaananen HK, Zhao H, Mulari M, Halleen JM. The cell biology of osteoclast function. J. Cell Sci., 2000, 113: 377-381

[114] Ajani JA, Levin B, Wallace S. Systemic and regional therapy of advanced islet cell tumors. Gastroenterol. Clin. North Am., 1989, 18: 923-930

[115] Hartman GD, Duggan ME. alpha(v)beta(3) Integrin antagonists as inhibitors of bone resorption. Expert Opin. Investig. Drugs, 2000, 9: 1281-1291

[116] Guasto A, Cormier-Daire V. Signaling pathways in bone development and their related skeletal dysplasia. Int. J. Mol. Sci, 2021, 22: 4321

[117] Capulli M, Paone R, Rucci N. Osteoblast and osteocyte: games without frontiers. Arch. Biochem. Biophys., 2014, 561: 3-12

[118] Matsuo K, Irie N. Osteoclast-osteoblast communication. Arch. Biochem. Biophys., 2008, 473: 201-209

[119] Knothe Tate ML, Adamson JR, Tami AE, Bauer TW. The osteocyte. Int. J. Biochem. Cell Biol., 2004, 36: 1-8

[120] Bonewald LF. The amazing osteocyte. J. Bone Miner. Res., 2011, 26: 229-238

[121] McDonald MM, et al.. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell, 2021, 184: 1330-1347.e1313

[122] Lassen NE, et al.. Coupling of bone resorption and formation in real time: new knowledge gained from human Haversian BMUs. J. Bone Miner. Res., 2017, 32: 1395-1405

[123] Kohli SS, Kohli VS. Role of RANKL-RANK/osteoprotegerin molecular complex in bone remodeling and its immunopathologic implications. Indian J. Endocrinol. Metab., 2011, 15: 175-181

[124] Walsh MC, Choi Y. Biology of the RANKL-RANK-OPG system in immunity, bone, and beyond. Front. Immunol., 2014, 5: 511

[125] Ono T, Hayashi M, Sasaki F, Nakashima T. RANKL biology: bone metabolism, the immune system, and beyond. Inflamm. Regen., 2020, 40: 2

[126] Takegahara N, Kim H, Choi Y. RANKL biology. Bone, 2022, 159 116353

[127] An J, et al.. Natural products for treatment of bone erosive diseases: the effects and mechanisms on inhibiting osteoclastogenesis and bone resorption. Int. Immunopharmacol., 2016, 36: 118-131

[128] AlQranei MS, Chellaiah MA. Osteoclastogenesis in periodontal diseases: Possible mediators and mechanisms. J. Oral. Biosci., 2020, 62: 123-130

[129] Kong YY, et al.. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature, 1999, 397: 315-323

[130] Dougall WC, et al.. RANK is essential for osteoclast and lymph node development. Genes Dev., 1999, 13: 2412-2424

[131] Mizuno A, et al.. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem. Biophys. Res. Commun., 1998, 247: 610-615

[132] Simonet WS, et al.. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell, 1997, 89: 309-319

[133] Ni S, Shan F, Geng J. Interleukin-10 family members: Biology and role in the bone and joint diseases. Int. Immunopharmacol., 2022, 108 108881

[134] Zhao B, Ivashkiv LB. Negative regulation of osteoclastogenesis and bone resorption by cytokines and transcriptional repressors. Arthritis Res. Ther., 2011, 13: 234

[135] Yao Z, Getting SJ, Locke IC. Regulation of TNF-induced osteoclast differentiation. Cells, 2021, 11: 132

[136] Zhou P, Zheng T, Zhao B. Cytokine-mediated immunomodulation of osteoclastogenesis. Bone, 2022, 164 116540

[137] Chen S, et al.. Macrophages in immunoregulation and therapeutics. Signal Transduct. Target Ther., 2023, 8: 207

[138] Viniegra A, et al.. Resolving macrophages counter osteolysis by anabolic actions on bone cells. J. Dent. Res., 2018, 97: 1160-1169

[139] Lee YN, et al.. c-Fos as a regulator of degranulation and cytokine production in FcepsilonRI-activated mast cells. J. Immunol., 2004, 173: 2571-2577

[140] Bozec A, et al.. Fra-2/AP-1 controls bone formation by regulating osteoblast differentiation and collagen production. J. Cell Biol., 2010, 190: 1093-1106

[141] Malnou CE, et al.. Heterodimerization with Jun family members regulates c-Fos nucleocytoplasmic traffic. J. Biol. Chem., 2007, 282: 31046-31059

[142] Matsuo K, et al.. Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation. Nat. Genet., 2000, 24: 184-187

[143] Wang ZQ, et al.. Bone and haematopoietic defects in mice lacking c-fos. Nature, 1992, 360: 741-745

[144] Grigoriadis AE, et al.. c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science, 1994, 266: 443-448

[145] Al Mamun MA, Asim MMH, Sahin MAZ, Al-Bari MAA. Flavonoids compounds from Tridax procumbens inhibit osteoclast differentiation by down-regulating c-Fos activation. J. Cell Mol. Med., 2020, 24: 2542-2551

[146] Wu X, et al.. Caffeic acid 3,4-dihydroxy-phenethyl ester suppresses receptor activator of NF-kappaB ligand-induced osteoclastogenesis and prevents ovariectomy-induced bone loss through inhibition of mitogen-activated protein kinase/activator protein 1 and Ca²⁺-nuclear factor of activated T-cells cytoplasmic 1 signaling pathways. J. Bone Miner. Res., 2012, 27: 1298-1308

[147] Yang J, Peng B. Correlation between the expression of c-Fos and osteoclasts in induced periapical lesions in rats. J. Endod., 2008, 34: 22-25

[148] Xu W, et al.. Chitooligosaccharide inhibits RANKL-induced osteoclastogenesis and ligation-induced periodontitis by suppressing MAPK/ c-fos/NFATC1 signaling. J. Cell Physiol., 2020, 235: 3022-3032

[149] Ray N, et al.. c-Fos suppresses systemic inflammatory response to endotoxin. Int. Immunol., 2006, 18: 671-677

[150] Zhang Z, et al.. Pirfenidone inhibits alveolar bone loss in ligature-induced periodontitis by suppressing the NF-kappaB signaling pathway in mice. Int. J. Mol. Sci., 2023, 24: 8682

[151] Jiang T, et al.. Role and regulation of transcription factors in osteoclastogenesis. Int. J. Mol. Sci., 2023, 24: 16175

[152] Kim JH, Kim N. Regulation of NFATc1 in osteoclast differentiation. J. Bone Metab., 2014, 21: 233-241

[153] Zhao Q, Shao J, Chen W, Li YP. Osteoclast differentiation and gene regulation. Front. Biosci., 2007, 12: 2519-2529

[154] Aliprantis AO, Glimcher LH. NFATc1 in inflammatory and musculoskeletal conditions. Adv. Exp. Med. Biol., 2010, 658: 69-75

[155] Zhao Q, Wang X, Liu Y, He A, Jia R. NFATc1: functions in osteoclasts. Int. J. Biochem. Cell Biol., 2010, 42: 576-579

[156] Greenblatt MB, et al.. NFATc1 and NFATc2 repress spontaneous osteoarthritis. Proc. Natl. Acad. Sci. USA, 2013, 110: 19914-19919

[157] Zhong H, SuYang H, Erdjument-Bromage H, Tempst P, Ghosh S. The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism. Cell, 1997, 89: 413-424

[158] Yamashita T, et al.. NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J. Biol. Chem., 2007, 282: 18245-18253

[159] Souza PP, Lerner UH. The role of cytokines in inflammatory bone loss. Immunol. Investig., 2013, 42: 555-622

[160] Zhang C, Yang L, Peng B. Critical role of NFATc1 in periapical lesions. Int. Endod. J., 2010, 43: 109-114

[161] Ihn HJ, et al.. A novel benzamide derivative protects ligature-induced alveolar bone erosion by inhibiting NFATc1-mediated osteoclastogenesis. Toxicol. Appl. Pharm., 2018, 355: 9-17

[162] Kim HJ, et al.. Myeloid-specific PTP1B deficiency attenuates inflammation-induced and ovariectomy-induced bone loss in mice by inhibiting osteoclastogenesis. J. Bone Miner. Res., 2022, 37: 505-514

[163] Da Ponte Leguizamon N, et al.. Phytocystatin CsinCPI-2 reduces osteoclastogenesis and alveolar bone loss. J. Dent. Res., 2022, 101: 216-225

[164] Miyamoto T. Regulators of osteoclast differentiation and cell-cell fusion. Keio J. Med., 2011, 60: 101-105

[165] Matsubara T, Yasuda K, Mizuta K, Kawaue H, Kokabu S. Tyrosine kinase Src is a regulatory factor of bone homeostasis. Int. J. Mol. Sci., 2022, 23: 5508

[166] Chen R, et al.. Roles of ubiquitin-specific proteases in inflammatory diseases. Front. Immunol., 2024, 15 1258740

[167] Abu-Amer Y, Ross FP, Edwards J, Teitelbaum SL. Lipopolysaccharide-stimulated osteoclastogenesis is mediated by tumor necrosis factor via its P55 receptor. J. Clin. Invest., 1997, 100: 1557-1565

[168] Mao HQ, et al.. STING inhibition alleviates bone resorption in apical periodontitis. Int. Endod. J., 2024, 57: 951-965

[169] Kleinert, H., Art, J. & Pautz, A. in Nitric Oxide (Second Edition) 211–267 (2010).

[170] Piiper A, Zeuzem S. Receptor tyrosine kinases are signaling intermediates of G protein-coupled receptors. Curr. Pharm. Des., 2004, 10: 3539-3545

[171] Ambili R, Santhi WS, Janam P, Nandakumar K, Pillai MR. Expression of activated transcription factor nuclear factor-kappaB in periodontally diseased tissues. J. Periodontol., 2005, 76: 1148-1153

[172] Garcia de Aquino S, et al.. Signaling pathways associated with the expression of inflammatory mediators activated during the course of two models of experimental periodontitis. Life Sci., 2009, 84: 745-754

[173] Hayden MS, Ghosh S. Regulation of NF-kappaB by TNF family cytokines. Semin Immunol., 2014, 26: 253-266

[174] Hinz M, Scheidereit C. The IkappaB kinase complex in NF-kappaB regulation and beyond. EMBO Rep., 2014, 15: 46-61

[175] Trares K, Ackermann J, Koch I. The canonical and non-canonical NF-kappaB pathways and their crosstalk: a comparative study based on Petri nets. Biosystems, 2022, 211 104564

[176] Sun SC. The non-canonical NF-kappaB pathway in immunity and inflammation. Nat. Rev. Immunol., 2017, 17: 545-558

[177] Snyder NA, Silva GM. Deubiquitinating enzymes (DUBs): regulation, homeostasis, and oxidative stress response. J. Biol. Chem., 2021, 297 101077

[178] Steelman LS, et al.. Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging, 2011, 3: 192-222

[179] Guo Q, et al.. NF-kappaB in biology and targeted therapy: new insights and translational implications. Signal Transduct. Target Ther., 2024, 9: 53

[180] Boyce BF, Li J, Yao Z, Xing L. Nuclear factor-kappa B regulation of osteoclastogenesis and osteoblastogenesis. Endocrinol. Metab., 2023, 38: 504-521

[181] Makarov SS, NF-kappa B. in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue destruction. Arthritis Res., 2001, 3: 200-206

[182] Roskoski RJr. Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharm. Res., 2016, 111: 784-803

[183] Chen X, et al.. Macrophage M1 polarization mediated via the IL-6/STAT3 pathway contributes to apical periodontitis induced by Porphyromonas gingivalis. J. Appl. Oral. Sci., 2022, 30 e20220316

[184] Arce M, et al.. Increased STAT3 activation in periodontitis drives inflammatory bone loss. J. Dent. Res., 2023, 102: 1366-1375

[185] Chaves de Souza JA, et al.. SOCS3 expression correlates with severity of inflammation, expression of proinflammatory cytokines, and activation of STAT3 and p38 MAPK in LPS-induced inflammation in vivo. Mediators Inflamm., 2013, 2013 650812

[186] Bahar ME, Kim HJ, Kim DR. Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Signal Transduct. Target Ther., 2023, 8: 455

[187] Lue H, Dewor M, Leng L, Bucala R, Bernhagen J. Activation of the JNK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on CXCR4 and CD74. Cell Signal, 2011, 23: 135-144

[188] Kaneko H, et al.. Inhibition of c-Jun N-terminal kinase signaling promotes osteoblastic differentiation of periodontal ligament stem cells and induces regeneration of periodontal tissues. Arch. Oral. Biol., 2022, 134 105323

[189] Amarasekara DS, et al.. Regulation of osteoclast differentiation by cytokine networks. Immune Netw., 2018, 18 e8

[190] Perdiguero E, Ruiz-Bonilla V, Serrano AL, Munoz-Canoves P. Genetic deficiency of p38alpha reveals its critical role in myoblast cell cycle exit: the p38alpha-JNK connection. Cell Cycle, 2007, 6: 1298-1303

[191] Wang Z, et al.. Phosphatase-mediated crosstalk control of ERK and p38 MAPK signaling in corneal epithelial cells. Investig. Ophthalmol. Vis. Sci., 2006, 47: 5267-5275

[192] Rogers JE, et al.. A p38 mitogen-activated protein kinase inhibitor arrests active alveolar bone loss in a rat periodontitis model. J. Periodontol., 2007, 78: 1992-1998

[193] Li Q, et al.. Silencing mitogen-activated protein kinase-activated protein kinase-2 arrests inflammatory bone loss. J. Pharm. Exp. Ther., 2011, 336: 633-642

[194] Jiang L, et al.. The proteasome inhibitor bortezomib inhibits inflammatory response of periodontal ligament cells and ameliorates experimental periodontitis in rats. J. Periodontol., 2017, 88: 473-483

[195] Liu C, et al.. Research on the role and mechanism of the PI3K/Akt/mTOR signalling pathway in osteoporosis. Front. Endocrinol., 2025, 16 1541714

[196] Kang H, Chang W, Hurley M, Vignery A, Wu D. Important roles of PI3Kgamma in osteoclastogenesis and bone homeostasis. Proc. Natl. Acad. Sci. USA, 2010, 107: 12901-12906

[197] Moon JB, et al.. Akt induces osteoclast differentiation through regulating the GSK3beta/NFATc1 signaling cascade. J. Immunol., 2012, 188: 163-169

[198] Wong BR, et al.. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol. Cell, 1999, 4: 1041-1049

[199] Lv, H. et al. Kurarinone mitigates LPS-induced inflammatory osteolysis by inhibiting osteoclastogenesis through the reduction of ROS levels and suppression of the PI3K/AKT signaling pathway. Inflammationhttps://doi.org/10.1007/s10753-025-02244-1 (2025).

[200] Tang Y, Pan J, Guo H, Li Q. Identification of an active fraction of Kangfuxin in the treatment of periodontitis in a rat model. Folia Histochem Cytobiol., 2024, 62: 133-144

[201] Wang W, et al.. Capsaicin attenuates Porphyromonas gingivalis-suppressed osteogenesis of periodontal ligament stem cells via regulating mitochondrial function and activating PI3K/AKT/mTOR pathway. J. Periodontal Res., 2024, 59: 798-811

[202] Yu C, et al.. Garlic-derived exosome-like nanovesicles: a promising natural nanotherapy for periodontitis via PHGDH/PI3K/AKT-mediated metabolic and inflammatory regulation. Int. J. Nanomed., 2025, 20: 5551-5572

[203] Liu J, et al.. Wnt/beta-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct. Target Ther., 2022, 7: 3

[204] Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene, 2017, 36: 1461-1473

[205] Bao J, Yang Y, Xia M, Sun W, Chen L. Wnt signaling: an attractive target for periodontitis treatment. Biomed. Pharmacother., 2021, 133 110935

[206] Duan P, Bonewald LF. The role of the wnt/beta-catenin signaling pathway in formation and maintenance of bone and teeth. Int. J. Biochem. Cell Biol., 2016, 77: 23-29

[207] Tu X, et al.. Osteocytes mediate the anabolic actions of canonical Wnt/beta-catenin signaling in bone. Proc. Natl. Acad. Sci. USA, 2015, 112: E478-486

[208] Zhou M, Graves DT. Impact of the host response and osteoblast lineage cells on periodontal disease. Front. Immunol., 2022, 13 998244

[209] Nishi H, Demir E, Panchenko AR. Crosstalk between signaling pathways provided by single and multiple protein phosphorylation sites. J. Mol. Biol., 2015, 427: 511-520

[210] Chu X, et al.. The role of senescence in experimental periodontitis at the causal level: an in vivo study. Cells, 2025, 14: 226

[211] Xu Y, Li N, Xiang R, Sun P. Emerging roles of the p38 MAPK and PI3K/AKT/mTOR pathways in oncogene-induced senescence. Trends Biochem. Sci., 2014, 39: 268-276

[212] Li H, et al.. Transcriptional factor HBP1 targets P16(INK4A), upregulating its expression and consequently is involved in Ras-induced premature senescence. Oncogene, 2010, 29: 5083-5094

[213] Borodkina A, Shatrova A, Abushik P, Nikolsky N, Burova E. Interaction between ROS dependent DNA damage, mitochondria and p38 MAPK underlies senescence of human adult stem cells. Aging, 2014, 6: 481-495

[214] Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J., 2011, 30: 1536-1548

[215] Yin M, Zheng X, Shi L. Targeting p38 MAPK: a potential bridge between ER stress and age-related bone loss. Cell Signal, 2025, 127 111549

[216] Oliveira GE, et al.. Exploring the impact of biological agents on protecting against experimental periodontitis: a systematic review of animal-based studies. Biomed. Res. Int., 2024, 2024 1716735

[217] Pavanelli ALR, et al.. Pharmacological therapies for the management of inflammatory bone resorption in periodontal disease: a review of preclinical studies. Biomed. Res. Int., 2022, 2022 5832009

[218] Boyce BF, et al.. Future anti-catabolic therapeutic targets in bone disease. Ann. N. Y. Acad. Sci., 2006, 1068: 447-457

[219] Yang B, Pang X, Li Z, Chen Z, Wang Y. Immunomodulation in the treatment of periodontitis: progress and perspectives. Front. Immunol., 2021, 12 781378

[220] Wu Y, et al.. Bone targeted nano-drug and nano-delivery. Bone Res., 2024, 12: 51

[221] Stapleton M, et al.. Development of bone targeting drugs. Int. J. Mol. Sci., 2017, 18: 1345

[222] de Molon RS, et al.. Evaluation of the host response in various models of induced periodontal disease in mice. J. Periodontol., 2014, 85: 465-477

[223] de Molon RS, et al.. Long-term evaluation of oral gavage with periodontopathogens or ligature induction of experimental periodontal disease in mice. Clin. Oral. Investig., 2016, 20: 1203-1216

[224] de Molon RS, Park CH, Jin Q, Sugai J, Cirelli JA. Characterization of ligature-induced experimental periodontitis. Microsc Res. Tech., 2018, 81: 1412-1421

[225] de Molon RS, de Avila ED, Cirelli JA. Host responses induced by different animal models of periodontal disease: a literature review. J. Investig. Clin. Dent., 2013, 4: 211-218

[226] Koide M, Kinugawa S, Takahashi N, Udagawa N. Osteoclastic bone resorption induced by innate immune responses. Periodontol 2000, 2010, 54: 235-246

[227] Silva BR, et al.. Establishing a dual murine model to explore the interactions between diabetes and periodontitis in mice. Int. J. Mol. Sci., 2025, 26: 5611

[228] Zhen L, Fan DS, Zhang Y, Cao XM, Wang LM. Resveratrol ameliorates experimental periodontitis in diabetic mice through negative regulation of TLR4 signaling. Acta Pharm. Sin., 2015, 36: 221-228

[229] Xiao CJ, Yu XJ, Xie JL, Liu S, Li S. Protective effect and related mechanisms of curcumin in rat experimental periodontitis. Head. Face Med., 2018, 14: 12

[230] Elburki MS, et al.. A chemically modified curcumin (CMC 2.24) inhibits nuclear factor kappaB activation and inflammatory bone loss in murine models of LPS-induced experimental periodontitis and diabetes-associated natural periodontitis. Inflammation, 2017, 40: 1436-1449

[231] Wong M, et al.. TNFalpha blockade in human diseases: mechanisms and future directions. Clin. Immunol., 2008, 126: 121-136

[232] Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol. Rev., 2018, 281: 8-27

[233] McIntyre KW, et al.. A highly selective inhibitor of I kappa B kinase, BMS-345541, blocks both joint inflammation and destruction in collagen-induced arthritis in mice. Arthritis Rheum., 2003, 48: 2652-2659

[234] Gillooly KM, et al.. Periodic, partial inhibition of IkappaB Kinase beta-mediated signaling yields therapeutic benefit in preclinical models of rheumatoid arthritis. J. Pharm. Exp. Ther., 2009, 331: 349-360

[235] Huang YK. IL-8 as a potential therapeutic target for periodontitis and its inhibition by caffeic acid phenethyl ester in vitro. Int. J. Mol. Sci., 2021, 22: 3641

[236] Aoki T, et al.. Inhibition of non-canonical NF-kappaB signaling suppresses periodontal inflammation and bone loss. Front. Immunol., 2023, 14 1179007

[237] Wang Y, et al.. AZD8835 inhibits osteoclastogenesis and periodontitis-induced alveolar bone loss in rats. J. Cell Physiol., 2019, 234: 10432-10444

[238] Jimi E, et al.. Selective inhibition of NF-kappa B blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo. Nat. Med., 2004, 10: 617-624

[239] Zhang Z, et al.. NAT10 regulates the LPS-induced inflammatory response via the NOX2-ROS-NF-kappaB pathway in macrophages. Biochim. Biophys. Acta Mol. Cell Res., 2023, 1870 119521

[240] Zhu Y, Qiao S, Pang Y, Wang H, Zhou Y. Deferoxamine treatment effectively prevents periodontitis progression by reducing inflammation and osteoclastogenesis in experimental periodontitis rats. J. Inflamm. Res., 2024, 17: 9637-9650

[241] Cafferata EA, et al.. Interleukin-35 inhibits alveolar bone resorption by modulating the Th17/Treg imbalance during periodontitis. J. Clin. Periodontol., 2020, 47: 676-688

[242] Li L, et al.. IL-37 alleviates alveolar bone resorption and inflammatory response through the NF-kappaB/NLRP3 signaling pathway in male mice with periodontitis. Arch. Oral. Biol., 2023, 147 105629

[243] Wang B, et al.. TPCA-1 negatively regulates inflammation mediated by NF-kappaB pathway in mouse chronic periodontitis model. Mol. Oral. Microbiol., 2021, 36: 192-201

[244] Wang J, et al.. Inhibition of nuclear factor kappa B inducing kinase suppresses inflammatory responses and the symptoms of chronic periodontitis in a mouse model. Int. J. Biochem. Cell Biol., 2021, 139 106052

[245] Girisa S, et al.. From simple mouth cavities to complex oral mucosal disorders-curcuminoids as a promising therapeutic approach. ACS Pharm. Transl. Sci., 2021, 4: 647-665

[246] Minagawa T, et al.. Resveratrol suppresses the inflammatory responses of human gingival epithelial cells in a SIRT1 independent manner. J. Periodontal Res., 2015, 50: 586-593

[247] Tan Y, Feng J, Xiao Y, Bao C. Grafting resveratrol onto mesoporous silica nanoparticles towards efficient sustainable immunoregulation and insulin resistance alleviation for diabetic periodontitis therapy. J. Mater. Chem. B, 2022, 10: 4840-4855

[248] Huangfu H, et al.. Facile engineering of resveratrol nanoparticles loaded with 20(S)-protopanaxadiol for the treatment of periodontitis by regulating the macrophage phenotype. Nanoscale, 2023, 15: 7894-7908

[249] Zhu Y, et al.. A Chitosan-based hydrogel to modulate immune cells and promote periodontitis healing in the high-fat diet-induced periodontitis rat model. Acta Biomater., 2025, 200: 452-463

[250] de Molon RS. Therapeutic potential of tanshinones in osteolytic diseases: from molecular and cellular pathways to preclinical models. Dent. J., 2025, 9: 309

[251] Pavanelli, A. L. R. et al. Anti-inflammatory and antiresorptive activities of tanshinone-IIA mitigate alveolar bone destruction in mice with experimental periodontitis. J. Periodontol.https://doi.org/10.1002/JPER.24-0618 (2025).

[252] Cafferata EA, et al.. Boldine inhibits the alveolar bone resorption during ligature-induced periodontitis by modulating the Th17/Treg imbalance. J. Periodontol., 2021, 92: 123-136

[253] Liu H, et al.. Hesperetin suppresses RANKL-induced osteoclastogenesis and ameliorates lipopolysaccharide-induced bone loss. J. Cell Physiol., 2019, 234: 11009-11022

[254] Goncalves VP, et al.. Systemic dietary hesperidin modulation of osteoclastogenesis, bone homeostasis and periodontal disease in mice. Int. J. Mol. Sci, 2022, 23: 7100

[255] Fu J, et al.. Lactobacillus rhamnosus inhibits osteoclast differentiation by suppressing the TLR2/NF-kappaB pathway. Oral. Dis., 2024, 30: 2373-2386

[256] Marotte H, Miossec P. Prevention of bone mineral density loss in patients with rheumatoid arthritis treated with anti-TNFalpha therapy. Biologics, 2008, 2: 663-669

[257] Goncalves DC, et al.. Infliximab attenuates inflammatory osteolysis in a model of periodontitis in Wistar rats. Exp. Biol. Med., 2014, 239: 442-453

[258] Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat. Rev. Drug Discov., 2012, 11: 633-652

[259] Wang F, et al.. IL-1beta receptor antagonist (IL-1Ra) combined with autophagy inducer (TAT-Beclin1) is an effective alternative for attenuating extracellular matrix degradation in rat and human osteoarthritis chondrocytes. Arthritis Res. Ther., 2019, 21: 171

[260] Lee SY, et al.. IL-1 receptor antagonist (IL-1Ra)-Fc ameliorate autoimmune arthritis by regulation of the Th17 cells/Treg balance and arthrogenic cytokine activation. Immunol. Lett., 2016, 172: 56-66

[261] Liu Y, et al.. Treatment of periodontal inflammation in diabetic rats with IL-1ra thermosensitive hydrogel. Int. J. Mol. Sci., 2022, 23: 13939

[262] Hashimoto T, et al.. Tocilizumab suppresses NF-kappa B activation via toll-like receptor 9 signaling by reducing cell-free DNA in rheumatoid arthritis. Clin. Exp. Immunol., 2023, 213: 209-220

[263] Apolinario Vieira GH, et al.. Specific inhibition of IL-6 receptor attenuates inflammatory bone loss in experimental periodontitis. J. Periodontol., 2021, 92: 1460-1469

[264] Koide M, et al.. Osteoprotegerin-deficient male mice as a model for severe alveolar bone loss: comparison with RANKL-overexpressing transgenic male mice. Endocrinology, 2013, 154: 773-782

[265] Cummings SR, et al.. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med., 2009, 361: 756-765

[266] Yuan H, Gupte R, Zelkha S, Amar S. Receptor activator of nuclear factor kappa B ligand antagonists inhibit tissue inflammation and bone loss in experimental periodontitis. J. Clin. Periodontol., 2011, 38: 1029-1036

[267] de Molon RS, et al.. Spontaneous osteonecrosis of the jaws in the maxilla of mice on antiresorptive treatment: a novel ONJ mouse model. Bone, 2014, 68: 11-19

[268] de Molon RS, et al.. OPG-Fc but not zoledronic acid discontinuation reverses osteonecrosis of the jaws (ONJ) in mice. J. Bone Miner. Res, 2015, 30: 1627-1640

[269] Soundia A, et al.. Osteonecrosis of the jaws (ONJ) in mice after extraction of teeth with periradicular disease. Bone, 2016, 90: 133-141

[270] de Molon RS, et al.. Rheumatoid arthritis exacerbates the severity of osteonecrosis of the jaws (ONJ) in mice. a randomized, prospective, controlled animal study. J. Bone Miner. Res., 2016, 31: 1596-1607

[271] Nakamura M, et al.. Osteoprotegerin regulates bone formation through a coupling mechanism with bone resorption. Endocrinology, 2003, 144: 5441-5449

[272] Jin Q, et al.. RANKL inhibition through osteoprotegerin blocks bone loss in experimental periodontitis. J. Periodontol., 2007, 78: 1300-1308

[273] Hamar A, et al.. Effects of one-year tofacitinib therapy on bone metabolism in rheumatoid arthritis. Osteoporos. Int., 2021, 32: 1621-1629

[274] Kobayashi T, Ito S, Murasawa A, Ishikawa H, Yoshie H. Effects of tofacitinib on the clinical features of periodontitis in patients with rheumatoid arthritis: two case reports. BMC Rheumatol., 2019, 3: 13

[275] Yarilina A, Xu K, Chan C, Ivashkiv LB. Regulation of inflammatory responses in tumor necrosis factor-activated and rheumatoid arthritis synovial macrophages by JAK inhibitors. Arthritis Rheum., 2012, 64: 3856-3866

[276] Li CH, et al.. Stattic inhibits RANKL-mediated osteoclastogenesis by suppressing activation of STAT3 and NF-kappaB pathways. Int. Immunopharmacol., 2018, 58: 136-144

[277] Li Q, Valerio MS, Kirkwood KL. MAPK usage in periodontal disease progression. J. Signal Transduct., 2012, 2012 308943

[278] Gu L, Ke Y, Gan J, Li X. Berberine suppresses bone loss and inflammation in ligature-induced periodontitis through promotion of the G protein-coupled estrogen receptor-mediated inactivation of the p38MAPK/NF-kappaB pathway. Arch. Oral. Biol., 2021, 122 104992

[279] Wang C, et al.. Role of berberine thermosensitive hydrogel in periodontitis via PI3K/AKT pathway in vitro. Int. J. Mol. Sci., 2023, 24: 6364

[280] Zhao B, et al.. Eupatilin suppresses osteoclastogenesis and periodontal bone loss by inhibiting the MAPKs/Siglec-15 pathway. Int. Immunopharmacol., 2024, 139 112720

[281] Chen Y, et al.. The effect of the Litcubanine A on the treatment of murine experimental periodontitis by inhibiting monocyte-macrophage chemotaxis and osteoclast differentiation. J. Periodontal Res., 2023, 58: 948-958

[282] Yang J, et al.. The effect of the root bark of Lycium chinense (Lycii Radicis Cortex) on experimental periodontitis and alveolar bone loss in Sprague-Dawley rats. Antioxidants, 2024, 13: 1332

[283] Kim JA, et al.. Napyradiomycin B4 suppresses RANKL-induced osteoclastogenesis and prevents alveolar bone destruction in experimental periodontitis. ACS Pharm. Transl. Sci., 2024, 7: 1023-1031

[284] Liu CL, et al.. Ugonin L inhibits osteoclast formation and promotes osteoclast apoptosis by inhibiting the MAPK and NF-kappaB pathways. Biomed. Pharmacother., 2023, 166 115392

[285] Shuai F, et al.. A nucleoside-based supramolecular hydrogel integrating localized self-delivery and immunomodulation for periodontitis treatment. Biomaterials, 2025, 316 123024

[286] Sun M, et al.. Ginsenoside Rb3 inhibits osteoclastogenesis via ERK/NF-kappaB signaling pathway in vitro and in vivo. Oral. Dis., 2023, 29: 3460-3471

[287] Wang Z, Zhan C, Zeng F, Wu S. A biopolymer-based and inflammation-responsive nanodrug for rheumatoid arthritis treatment via inhibiting JAK-STAT and JNK signalling pathways. Nanoscale, 2020, 12: 23013-23027

[288] Han Z, et al.. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J. Clin. Invest., 2001, 108: 73-81

[289] Sun Y, et al.. Intermittent hyperglycaemia induces macrophage dysfunction by extracellular regulated protein kinase-dependent PKM2 translocation in periodontitis. Cell Prolif., 2024, 57 e13651

[290] Ihn HJ, et al.. PF-3845, a fatty acid amide hydrolase inhibitor, directly suppresses osteoclastogenesis through ERK and NF-kappaB pathways in vitro and alveolar bone loss in vivo. Int. J. Mol. Sci., 2021, 22: 1915

[291] Goldstein DM, Gabriel T. Pathway to the clinic: inhibition of P38 MAP kinase. A review of ten chemotypes selected for development. Curr. Top. Med. Chem., 2005, 5: 1017-1029

[292] Pargellis C, Regan J. Inhibitors of p38 mitogen-activated protein kinase for the treatment of rheumatoid arthritis. Curr. Opin. Investig. Drugs, 2003, 4: 566-571

[293] Patil CS, Kirkwood KL. p38 MAPK signaling in oral-related diseases. J. Dent. Res., 2007, 86: 812-825

[294] Cao J, et al.. Kaempferol combats the osteogenic differentiation damage of periodontal ligament stem cells in periodontitis via regulating EphrinB2-mediated PI3K/Akt and P38 pathways. Phytomedicine, 2025, 141 156733

[295] Mu H, et al.. Inhibition of fibulin-3 ameliorates periodontal inflammation through reducing M1 macrophage polarization via EGFR/PI3K/AKT pathway. J. Periodontol., 2025, 96: 440-454

[296] Socransky SS, Haffajee AD, Goodson JM, Lindhe J. New concepts of destructive periodontal disease. J. Clin. Periodontol., 1984, 11: 21-32

[297] Goodson JM, Tanner AC, Haffajee AD, Sornberger GC, Socransky SS. Patterns of progression and regression of advanced destructive periodontal disease. J. Clin. Periodontol., 1982, 9: 472-481

[298] Graves DT, Fine D, Teng YT, Van Dyke TE, Hajishengallis G. The use of rodent models to investigate host-bacteria interactions related to periodontal diseases. J. Clin. Periodontol., 2008, 35: 89-105

[299] Kinney JS, et al.. Saliva/pathogen biomarker signatures and periodontal disease progression. J. Dent. Res., 2011, 90: 752-758

[300] Ramseier CA, et al.. Identification of pathogen and host-response markers correlated with periodontal disease. J. Periodontol., 2009, 80: 436-446

[301] Yilmaz B, et al.. Dual-drug carboxymethyl chitosan hydrogel: development, characterization, and in vitro evaluation for periodontal therapy. Carbohydr. Polym., 2025, 363 123726

[302] Yin B, et al.. Smart injectable hydrogels for periodontal regeneration: Recent advancements in biomaterials and biofabrication strategies. Mater. Today Bio, 2025, 32 101855

[303] Nakajima M, et al.. Advances in local drug delivery for periodontal treatment: present strategies and future directions. Biomolecules, 2025, 15: 903

[304] Hashim NT, et al.. New insights in natural bioactive compounds for periodontal disease: advanced molecular mechanisms and therapeutic potential. Molecules, 2025, 30: 807

[305] Lopez-Valverde N, et al.. Antioxidant, anti-inflammatory and antimicrobial activity of natural products in periodontal disease: a comprehensive review. Front. Bioeng. Biotechnol., 2023, 11 1226907

[306] Anwar MA, et al.. Herbal remedies for oral and dental health: a comprehensive review of their multifaceted mechanisms including antimicrobial, anti-inflammatory, and antioxidant pathways. Inflammopharmacology, 2025, 33: 1085-1160

[307] Hashim NT, et al.. Natural bioactive compounds in the management of periodontal diseases: a comprehensive review. Molecules, 2024, 29: 3044

Funding

Sao Paulo Research Foundation - Fundacao de Amparo a Pesquisa do Estado de Sao Pulo (FAPESP). Grant number #2023/15750-7 Coordination for the Improvement of Higher Education Personnel - Grant number #88887.194785/2018-00

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