1. Please check and comment entries here.
Table of Contents

    Topic review

    Microbe-Associated Bone Cell Differentiation

    View times: 16
    Submitted by: Seung Hyun Han


    Gut microbiota has emerged as an important regulator of bone homeostasis. In particular, the modulation of innate immunity and bone homeostasis is mediated through the interaction between microbe-associated molecular patterns (MAMPs) and the host pattern recognition receptors including Toll-like receptors and nucleotide-binding oligomerization domains. Pathogenic bacteria such as Porphyromonas gingivalis and Staphylococcus aureus tend to induce bone destruction and cause various inflammatory bone diseases including periodontal diseases, osteomyelitis, and septic arthritis. On the other hand, probiotic bacteria such as Lactobacillus and Bifidobacterium species can prevent bone loss. In addition, bacterial metabolites and various secretory molecules such as short chain fatty acids and cyclic nucleotides can also affect bone homeostasis.

    1. Introduction

    The bone remodeling process is regulated by representative bone cells known as osteoclasts and osteoblasts [1]. The balance between bone-resorbing osteoclasts and bone-forming osteoblasts is essential for maintaining bone homeostasis [2]. However, imbalance between bone resorption and formation could lead to bone diseases [3]. Excessive osteoclast activity causes various bone diseases including osteoporosis, septic arthritis, osteomyelitis, and alveolar bone loss in periodontal diseases [4][5][6]. Especially, bacterial infections can directly affect bone homeostasis by increasing osteoclast differentiation and activation and/or decreasing osteoblast differentiation and activation [7]. For example, Streptococcus pyogenes, Staphylococcus aureus, and Neisseria gonorrhoeae are commonly found in patients with septic arthritis, resulting in cartilage and bone destruction within the joint [8]. Staphylococcus species such as S. aureus and Staphylococcus epidermidis are etiological agents of osteomyelitis [5]. Major oral pathogens, including Porphyromonas gingivalis and Fusobacterium nucleatum, are associated with periodontal diseases, manifesting alveolar bone loss [9]. However, unlike those pathogens, probiotics which are microorganisms that offer health benefits to the hosts are known to increase mineral density and volume of the bone [10]. For instance, Lactobacillus reuteri and Lactobacillus rhamnosus GG upregulate bone volume of mice [11][12]. In addition, other probiotics such as Lactobacillus gasseri and Lactobacillus brevis reduce bone loss and inflammation in mouse periodontitis model [13][14].
    Bacteria have unique structural components called microbe-associated molecular patterns (MAMPs) including lipopolysaccharide (LPS), lipoteichoic acid (LTA), lipoprotein (LPP), and peptidoglycan (PGN) [15]. The recognition of MAMPs by pattern recognition receptors (PRRs) is crucial for inducing host immune responses [15]. In addition, secretory microbial molecules including short chain fatty acid (SCFA), extracellular vesicle (EV), extracellular polysaccharide, and cyclic dinucleotide (CDN) also modulate bone cells [16][17][18]. Therefore, for a clear understanding of the regulation of bone metabolism by bacteria, it is essential to understand the effects of MAMPs and secretory microbial molecules on bone cells and their regulatory mechanism.

    2. Microbe-Associated Molecular Patterns

    MAMPs are structural or secretory molecules that are highly conserved in most microbes [19]. Well-known MAMPs are bacterial polysaccharides (LPS and LTA), surface proteins (LPP and adhesin), PGNs, and secretory molecules (SCFA, EV, extracellular polysaccharide, and CDN) [20]. These MAMPs can be sensed by various host PRRs, such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), or G-protein coupled receptors (GPCRs) [21][22]. Indeed, there are many host PRRs classified according to their location, function, and ligand specificity [23]. There are typically four types of PRRs: TLRs, NLRs, C-type lectin receptors, and RIG-1 like receptors [21]. Among these, TLRs localized at plasma membrane or in endosomes and NLRs localized in cytoplasm are the major PRRs in recognizing bacterial MAMPs [21]. For instance, TLR4 senses LPS, and TLR2 senses LPP and LTA [24]. On the other hand, NOD1 and NOD2 recognize bacterial PGNs through their distinct structural moieties, d-glutamyl-meso-diaminopimelic acid (iE-DAP) and muramyl dipeptide (MDP), respectively [25]. Based on their displayed patterns, each host receptor responds to its specific bacterial ligand, subsequently producing anti- or pro-inflammatory cytokines and chemokines to counteract against invading microbes [26]. It has been reported that pathogens or probiotics and their MAMPs could also affect osteoimmunological responses (Table 1) [27]. Therefore, we will focus on MAMPs and their effects on bone homeostasis in this section.
    Table 1. Effects of cell wall components on bone metabolism.







    Inducing bone loss

    Inhibiting osteoclastogenesis on macrophages

    Facilitating osteoclast differentiation on committed osteoclasts

    Downregulating osteoblast differentiation


    Lipoteichoic acid


    Healing femoral fractures in mice

    Attenuating osteoclast differentiation and activating phagocytosis

    Upregulating osteogenic markers and osteoblastogenesis




    Promoting bone resorption

    Upregulating osteoclast differentiation

    Stimulating osteoblasts to elevate RANKL/OPG ratio




    Inducing osteoclastogenesis and bone resorption




    Enhancing osteoclastogenesis and bone resorption

    Triggering osteoclast differentiation synergistically with LPS



    Upregulation of bone density

    Facilitating osteoblast differentiation

    Diminishing osteoclastogenesis by reducing RANKL/OPG ratio


    3. Therapeutics

    Microbes influence bone metabolism by constant interaction with host using their various MAMPs (Table 2) [7]. In infectious condition, MAMPs often trigger immoderate osteoclastogenesis or inhibit osteoblast differentiation through the activation of immune responses, causing bone diseases such as osteomyelitis, osteoporosis, and periodontitis [7]. Antibiotics are commonly used to treat MAMP-induced bone diseases in bacterial infection [58]. Nevertheless, the emergence of antibiotic-resistant bacteria and remaining MAMPs after treatment pose significant challenge for complete clearance [59]. Therefore, further studies are needed to understand the role of MAMPs in bone diseases and to control the immune responses induced by MAMPs.
    Table 2. Effects of secretory microbial molecules on bone metabolism.



    Effects on Bone Metabolism


    Short chain fatty acids

    Activation of GPCRs

    Inhibition of histone deacetylases

    Inhibited osteoclast differentiation and function

    Upregulated osteogenic factors in low dose

    Attenuated osteoblast differentiation and mineralization

    Prevented bone loss in various mouse models


    Extracellular vesicles

    Activation of TLR2

    Induction of pro-inflammatory cytokines

    Downregulated osteoblast differentiation and activity

    Regulated RANKL and OPG expression in mesenchymal cells


    Extracellular polysaccharides

    Activation of TLR2

    Inhibited osteoclast differentiation from macrophages, but some EPS increased collagenolytic activity of osteoclasts

    Enhanced osteoblast differentiation, but oral pathogen-derived CPS decreased proliferation of osteoblasts


    Cyclic dinucleotides

    Induction of STING-mediated IFN-β

    Inhibited differentiation of macropahges into mature osteoclasts

    Alleviated RANKL-induced bone destruction


    On the other hand, several studies investigated that some MAMPs, especially derived from probiotics, decrease bone resorption or enhance bone formation by controlling the differentiation of osteoclasts or osteoblasts, respectively, in both in vitro and in vivo studies [18][57][63]. Many therapeutic drugs, such as bisphosphonates, monoclonal antibodies, or hormone preparations, are traditionally developed to treat bone diseases by inhibiting bone resorption or inducing bone formation [68][69][70]. However, conventional drugs show unexpected side effects, such as nausea or osteonecrosis of jaw [70][71][72]. Therefore, we suggest that probiotic-derived MAMPs could alternatively be used in place of conventional therapies. To evaluate their therapeutic use, we have discussed below how to treat MAMP-induced bone diseases and how to exploit MAMPs in bone health.

    The entry is from 10.3390/ijms22115805


    1. Kular, J.; Tickner, J.; Chim, S.M.; Xu, J. An overview of the regulation of bone remodelling at the cellular level. Clin. Biochem. 2012, 45, 863–873.
    2. Robling, A.G.; Castillo, A.B.; Turner, C.H. Biomechanical and molecular regulation of bone remodeling. Annu. Rev. Biomed. Eng. 2006, 8, 455–498.
    3. Feng, X.; McDonald, J.M. Disorders of bone remodeling. Annu. Rev. Pathol. 2011, 6, 121–145.
    4. Krauss, J.L.; Roper, P.M.; Ballard, A.; Shih, C.C.; Fitzpatrick, J.A.J.; Cassat, J.E.; Ng, P.Y.; Pavlos, N.J.; Veis, D.J. Staphylococcus aureus Infects Osteoclasts and Replicates Intracellularly. mBio 2019, 10.
    5. Wright, J.A.; Nair, S.P. Interaction of staphylococci with bone. Int. J. Med. Microbiol. 2010, 300, 193–204.
    6. Martin, T.R.; Mathison, J.C.; Tobias, P.S.; Leturcq, D.J.; Moriarty, A.M.; Maunder, R.J.; Ulevitch, R.J. Lipopolysaccharide binding protein enhances the responsiveness of alveolar macrophages to bacterial lipopolysaccharide. Implications for cytokine production in normal and injured lungs. J. Clin. Investig. 1992, 90, 2209–2219.
    7. Charles, J.F.; Nakamura, M.C. Bone and the innate immune system. Curr. Osteoporos. Rep. 2014, 12, 1–8.
    8. Sakurai, A.; Okahashi, N.; Nakagawa, I.; Kawabata, S.; Amano, A.; Ooshima, T.; Hamada, S. Streptococcus pyogenes infection induces septic arthritis with increased production of the receptor activator of the NF-kappaB ligand. Infect. Immun. 2003, 71, 6019–6026.
    9. Binder Gallimidi, A.; Fischman, S.; Revach, B.; Bulvik, R.; Maliutina, A.; Rubinstein, A.M.; Nussbaum, G.; Elkin, M. Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model. Oncotarget 2015, 6, 22613–22623.
    10. Parvaneh, K.; Jamaluddin, R.; Karimi, G.; Erfani, R. Effect of probiotics supplementation on bone mineral content and bone mass density. Sci. World J. 2014, 2014, 595962.
    11. Li, J.Y.; Chassaing, B.; Tyagi, A.M.; Vaccaro, C.; Luo, T.; Adams, J.; Darby, T.M.; Weitzmann, M.N.; Mulle, J.G.; Gewirtz, A.T.; et al. Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics. J. Clin. Investig. 2016, 126, 2049–2063.
    12. McCabe, L.R.; Irwin, R.; Schaefer, L.; Britton, R.A. Probiotic use decreases intestinal inflammation and increases bone density in healthy male but not female mice. J. Cell. Physiol. 2013, 228, 1793–1798.
    13. Kobayashi, R.; Kobayashi, T.; Sakai, F.; Hosoya, T.; Yamamoto, M.; Kurita-Ochiai, T. Oral administration of Lactobacillus gasseri SBT2055 is effective in preventing Porphyromonas gingivalis-accelerated periodontal disease. Sci. Rep. 2017, 7, 545.
    14. Maekawa, T.; Hajishengallis, G. Topical treatment with probiotic Lactobacillus brevis CD2 inhibits experimental periodontal inflammation and bone loss. J. Periodontal Res. 2014, 49, 785–791.
    15. Chu, H.; Mazmanian, S.K. Innate immune recognition of the microbiota promotes host-microbial symbiosis. Nat. Immunol. 2013, 14, 668–675.
    16. Iwami, K.; Moriyama, T. Effects of short chain fatty acid, sodium butyrate, on osteoblastic cells and osteoclastic cells. Int. J. Biochem. 1993, 25, 1631–1635.
    17. Song, M.K.; Kim, H.Y.; Choi, B.K.; Kim, H.H. Filifactor alocis-derived extracellular vesicles inhibit osteogenesis through TLR2 signaling. Mol. Oral Microbiol. 2020, 35, 202–210.
    18. Kwon, Y.; Park, O.J.; Kim, J.; Cho, J.H.; Yun, C.H.; Han, S.H. Cyclic Dinucleotides Inhibit Osteoclast Differentiation Through STING-Mediated Interferon-beta Signaling. J. Bone Miner. Res. 2019, 34, 1366–1375.
    19. Boller, T.; Felix, G. A renaissance of elicitors: Perception of microbe-associated molecular patterns and danger signals by pattern-recognition receptors. Annu. Rev. Plant Biol. 2009, 60, 379–406.
    20. Choi, H.W.; Klessig, D.F. DAMPs, MAMPs, and NAMPs in plant innate immunity. BMC Plant Biol. 2016, 16, 232.
    21. Akira, S.; Uematsu, S.; Takeuchi, O. Pathogen recognition and innate immunity. Cell 2006, 124, 783–801.
    22. Sun, M.; Wu, W.; Liu, Z.; Cong, Y. Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases. J. Gastroenterol. 2017, 52, 1–8.
    23. Brubaker, S.W.; Bonham, K.S.; Zanoni, I.; Kagan, J.C. Innate immune pattern recognition: A cell biological perspective. Annu. Rev. Immunol. 2015, 33, 257–290.
    24. Kawai, T.; Akira, S. TLR signaling. Semin. Immunol. 2007, 19, 24–32.
    25. Platnich, J.M.; Muruve, D.A. NOD-like receptors and inflammasomes: A review of their canonical and non-canonical signaling pathways. Arch. Biochem. Biophys. 2019, 670, 4–14.
    26. Chatterjee, S.; Jungraithmayr, W.; Bagchi, D. Immunity and Inflammation in Health and Disease: Emerging Roles of Nutraceuticals and Functional Foods in Immune Support; Academic Press: London, UK, 2018; pp. 175–187.
    27. D’Amelio, P.; Sassi, F. Gut Microbiota, Immune System, and Bone. Calcif. Tissue Int. 2018, 102, 415–425.
    28. Chen, M.F.; Chang, C.H.; Hu, C.C.; Wu, Y.Y.; Chang, Y.; Ueng, S.W.N. Periprosthetic Joint Infection Caused by Gram-Positive Versus Gram-Negative Bacteria: Lipopolysaccharide, but not Lipoteichoic Acid, Exerts Adverse Osteoclast-Mediated Effects on the Bone. J. Clin. Med. 2019, 8, 1289.
    29. Ridwan, R.D.; Sidarningsih, T.K.; Salim, S. Effect of lipopolysaccharide derived from surabaya isolates of Actinobacillus actinomycetemcomitans on alveolar bone destruction. Vet. World 2018, 11, 161–166.
    30. Nishihara, T.; Ishihara, Y.; Koseki, T.; Boutsi, E.A.; Senpuku, H.; Hanada, N. Membrane-associated interleukin-1 on macrophages stimulated with Actinobacillus actinomycetemcomitans lipopolysaccharide induces osteoclastic bone resorption in vivo. Cytobios 1995, 81, 229–237.
    31. Zou, W.; Bar-Shavit, Z. Dual modulation of osteoclast differentiation by lipopolysaccharide. J. Bone Miner. Res. 2002, 17, 1211–1218.
    32. Liu, J.; Wang, S.; Zhang, P.; Said-Al-Naief, N.; Michalek, S.M.; Feng, X. Molecular mechanism of the bifunctional role of lipopolysaccharide in osteoclastogenesis. J. Biol. Chem. 2009, 284, 12512–12523.
    33. Kadono, H.; Kido, J.; Kataoka, M.; Yamauchi, N.; Nagata, T. Inhibition of osteoblastic cell differentiation by lipopolysaccharide extract from Porphyromonas gingivalis. Infect. Immun. 1999, 67, 2841–2846.
    34. Tomomatsu, N.; Aoki, K.; Alles, N.; Soysa, N.S.; Hussain, A.; Nakachi, H.; Kita, S.; Shimokawa, H.; Ohya, K.; Amagasa, T. LPS-induced inhibition of osteogenesis is TNF-alpha dependent in a murine tooth extraction model. J. Bone Miner. Res. 2009, 24, 1770–1781.
    35. Bandow, K.; Maeda, A.; Kakimoto, K.; Kusuyama, J.; Shamoto, M.; Ohnishi, T.; Matsuguchi, T. Molecular mechanisms of the inhibitory effect of lipopolysaccharide (LPS) on osteoblast differentiation. Biochem. Biophys. Res. Commun. 2010, 402, 755–761.
    36. Yang, J.; Park, O.J.; Kim, J.; Baik, J.E.; Yun, C.H.; Han, S.H. Lipoteichoic Acid of Enterococcus faecalis Inhibits the Differentiation of Macrophages into Osteoclasts. J. Endod. 2016, 42, 570–574.
    37. Wang, S.; Heng, B.C.; Qiu, S.; Deng, J.; Shun Pan Cheung, G.; Jin, L.; Zhao, B.; Zhang, C. Lipoteichoic acid of Enterococcus faecalis inhibits osteoclastogenesis via transcription factor RBP-J. Innate Immun. 2019, 25, 13–21.
    38. Yang, J.; Ryu, Y.H.; Yun, C.H.; Han, S.H. Impaired osteoclastogenesis by staphylococcal lipoteichoic acid through Toll-like receptor 2 with partial involvement of MyD88. J. Leukoc. Biol. 2009, 86, 823–831.
    39. Liu, X.; Wang, Y.; Cao, Z.; Dou, C.; Bai, Y.; Liu, C.; Dong, S.; Fei, J. Staphylococcal lipoteichoic acid promotes osteogenic differentiation of mouse mesenchymal stem cells by increasing autophagic activity. Biochem. Biophys. Res. Commun. 2017, 485, 421–426.
    40. Hu, C.C.; Chang, C.H.; Hsiao, Y.M.; Chang, Y.; Wu, Y.Y.; Ueng, S.W.N.; Chen, M.F. Lipoteichoic Acid Accelerates Bone Healing by Enhancing Osteoblast Differentiation and Inhibiting Osteoclast Activation in a Mouse Model of Femoral Defects. Int. J. Mol. Sci. 2020, 21, 5550.
    41. Kim, J.; Yang, J.; Park, O.J.; Kang, S.S.; Kim, W.S.; Kurokawa, K.; Yun, C.H.; Kim, H.H.; Lee, B.L.; Han, S.H. Lipoproteins are an important bacterial component responsible for bone destruction through the induction of osteoclast differentiation and activation. J. Bone Miner. Res. 2013, 28, 2381–2391.
    42. Sato, N.; Takahashi, N.; Suda, K.; Nakamura, M.; Yamaki, M.; Ninomiya, T.; Kobayashi, Y.; Takada, H.; Shibata, K.; Yamamoto, M.; et al. MyD88 but not TRIF is essential for osteoclastogenesis induced by lipopolysaccharide, diacyl lipopeptide, and IL-1alpha. J. Exp. Med. 2004, 200, 601–611.
    43. Souza, J.A.C.; Magalhaes, F.A.C.; Oliveira, G.; RS, D.E.M.; Zuanon, J.A.; Souza, P.P.C. Pam2CSK4 (TLR2 agonist) induces periodontal destruction in mice. Braz. Oral Res. 2020, 34, e012.
    44. Sasaki, H.; Watanabe, K.; Toyama, T.; Koyata, Y.; Hamada, N. Porphyromonas gulae 41-kDa fimbriae induced osteoclast differentiation and cytokine production. J. Vet. Med. Sci. 2015, 77, 265–271.
    45. Hiramine, H.; Watanabe, K.; Hamada, N.; Umemoto, T. Porphyromonas gingivalis 67-kDa fimbriae induced cytokine production and osteoclast differentiation utilizing TLR2. FEMS Microbiol. Lett. 2003, 229, 49–55.
    46. Kawata, Y.; Hanazawa, S.; Amano, S.; Murakami, Y.; Matsumoto, T.; Nishida, K.; Kitano, S. Porphyromonas gingivalis fimbriae stimulate bone resorption in vitro. Infect. Immun. 1994, 62, 3012–3016.
    47. Hanazawa, S.; Kawata, Y.; Murakami, Y.; Naganuma, K.; Amano, S.; Miyata, Y.; Kitano, S. Porphyromonas gingivalis fimbria-stimulated bone resorption in vitro is inhibited by a tyrosine kinase inhibitor. Infect. Immun. 1995, 63, 2374–2377.
    48. Zhang, W.; Ju, J.; Rigney, T.; Tribble, G.D. Fimbriae of Porphyromonas gingivalis are important for initial invasion of osteoblasts, but not for inhibition of their differentiation and mineralization. J. Periodontol. 2011, 82, 909–916.
    49. Zhang, W.; Ju, J.; Rigney, T.; Tribble, G. Integrin alpha5beta1-fimbriae binding and actin rearrangement are essential for Porphyromonas gingivalis invasion of osteoblasts and subsequent activation of the JNK pathway. BMC Microbiol. 2013, 13, 5.
    50. Kishimoto, T.; Kaneko, T.; Ukai, T.; Yokoyama, M.; Ayon Haro, R.; Yoshinaga, Y.; Yoshimura, A.; Hara, Y. Peptidoglycan and lipopolysaccharide synergistically enhance bone resorption and osteoclastogenesis. J. Periodontal Res. 2012, 47, 446–454.
    51. Ozaki, Y.; Kishimoto, T.; Yamashita, Y.; Kaneko, T.; Higuchi, K.; Mae, M.; Oohira, M.; Mohammad, A.I.; Yanagiguchi, K.; Yoshimura, A. Expression of osteoclastogenic and anti-osteoclastogenic cytokines differs in mouse gingiva injected with lipopolysaccharide, peptidoglycan, or both. Arch. Oral Biol. 2021, 122, 104990.
    52. Ishida, M.; Kitaura, H.; Kimura, K.; Sugisawa, H.; Aonuma, T.; Takada, H.; Takano-Yamamoto, T. Muramyl dipeptide enhances lipopolysaccharide-induced osteoclast formation and bone resorption through increased RANKL expression in stromal cells. J. Immunol. Res. 2015, 2015, 132765.
    53. Sato, T.; Watanabe, K.; Kumada, H.; Toyama, T.; Tani-Ishii, N.; Hamada, N. Peptidoglycan of Actinomyces naeslundii induces inflammatory cytokine production and stimulates osteoclastogenesis in alveolar bone resorption. Arch. Oral Biol. 2012, 57, 1522–1528.
    54. Chaves de Souza, J.A.; Frasnelli, S.C.; Curylofo-Zotti, F.A.; Avila-Campos, M.J.; Spolidorio, L.C.; Zamboni, D.S.; Graves, D.T.; Rossa, C., Jr. NOD1 in the modulation of host-microbe interactions and inflammatory bone resorption in the periodontal disease model. Immunology 2016, 149, 374–385.
    55. Kitaura, H.; Ishida, M.; Kimura, K.; Sugisawa, H.; Kishikawa, A.; Shima, K.; Ogawa, S.; Qi, J.; Shen, W.R. Role of Muramyl Dipeptide in Lipopolysaccharide-Mediated Biological Activity and Osteoclast Activity. Anal. Cell. Pathol. 2018, 2018, 8047610.
    56. Jiao, Y.; Darzi, Y.; Tawaratsumida, K.; Marchesan, J.T.; Hasegawa, M.; Moon, H.; Chen, G.Y.; Nunez, G.; Giannobile, W.V.; Raes, J.; et al. Induction of bone loss by pathobiont-mediated Nod1 signaling in the oral cavity. Cell Host Microbe 2013, 13, 595–601.
    57. Park, O.J.; Kim, J.; Yang, J.; Yun, C.H.; Han, S.H. Muramyl Dipeptide, a Shared Structural Motif of Peptidoglycans, Is a Novel Inducer of Bone Formation through Induction of Runx2. J. Bone Miner. Res. 2017, 32, 1455–1468.
    58. Cortes-Penfield, N.W.; Kulkarni, P.A. The History of Antibiotic Treatment of Osteomyelitis. Open Forum Infect. Dis. 2019, 6, ofz181.
    59. Handel, A.; Margolis, E.; Levin, B.R. Exploring the role of the immune response in preventing antibiotic resistance. J. Theor. Biol. 2009, 256, 655–662.
    60. Chang, M.C.; Chen, Y.J.; Lian, Y.C.; Chang, B.E.; Huang, C.C.; Huang, W.L.; Pan, Y.H.; Jeng, J.H. Butyrate Stimulates Histone H3 Acetylation, 8-Isoprostane Production, RANKL Expression, and Regulated Osteoprotegerin Expression/Secretion in MG-63 Osteoblastic Cells. Int. J. Mol. Sci. 2018, 19, 4071.
    61. Montalvany-Antonucci, C.C.; Duffles, L.F.; de Arruda, J.A.A.; Zicker, M.C.; de Oliveira, S.; Macari, S.; Garlet, G.P.; Madeira, M.F.M.; Fukada, S.Y.; Andrade, I., Jr.; et al. Short-chain fatty acids and FFAR2 as suppressors of bone resorption. Bone 2019, 125, 112–121.
    62. Morozumi, A. High concentration of sodium butyrate suppresses osteoblastic differentiation and mineralized nodule formation in ROS17/2.8 cells. J. Oral Sci. 2011, 53, 509–516.
    63. Lucas, S.; Omata, Y.; Hofmann, J.; Bottcher, M.; Iljazovic, A.; Sarter, K.; Albrecht, O.; Schulz, O.; Krishnacoumar, B.; Kronke, G.; et al. Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss. Nat. Commun. 2018, 9, 55.
    64. Wallimann, A.; Hildebrand, M.; Groeger, D.; Stanic, B.; Akdis, C.A.; Zeiter, S.; Richards, R.G.; Moriarty, T.F.; O’Mahony, L.; Thompson, K. An Exopolysaccharide Produced by Bifidobacterium longum 35624(R) Inhibits Osteoclast Formation via a TLR2-Dependent Mechanism. Calcif. Tissue Int. 2021, 108, 654–666.
    65. Zanchetta, P.; Lagarde, N.; Guezennec, J. A new bone-healing material: A hyaluronic acid-like bacterial exopolysaccharide. Calcif. Tissue Int. 2003, 72, 74–79.
    66. Velasco, C.R.; Baud’huin, M.; Sinquin, C.; Maillasson, M.; Heymann, D.; Colliec-Jouault, S.; Padrines, M. Effects of a sulfated exopolysaccharide produced by Altermonas infernus on bone biology. Glycobiology 2011, 21, 781–795.
    67. Yamamoto, S.; Mogi, M.; Kinpara, K.; Ishihara, Y.; Ueda, N.; Amano, K.; Nishihara, T.; Noguchi, T.; Togari, A. Anti-proliferative capsular-like polysaccharide antigen from Actinobacillus actinomycetemcomitans induces apoptotic cell death in mouse osteoblastic MC3T3-E1 cells. J. Dent. Res. 1999, 78, 1230–1237.
    68. Drake, M.T.; Clarke, B.L.; Khosla, S. Bisphosphonates: Mechanism of action and role in clinical practice. Mayo Clin. Proc. 2008, 83, 1032–1045.
    69. Hanley, D.A.; Adachi, J.D.; Bell, A.; Brown, V. Denosumab: Mechanism of action and clinical outcomes. Int. J. Clin. Pract. 2012, 66, 1139–1146.
    70. Nikitovic, D.; Kavasi, R.M.; Berdiaki, A.; Papachristou, D.J.; Tsiaoussis, J.; Spandidos, D.A.; Tsatsakis, A.M.; Tzanakakis, G.N. Parathyroid hormone/parathyroid hormone-related peptide regulate osteosarcoma cell functions: Focus on the extracellular matrix (Review). Oncol. Rep. 2016, 36, 1787–1792.
    71. Kyrgidis, A.; Toulis, K.A. Denosumab-related osteonecrosis of the jaws. Osteoporos. Int. 2011, 22, 369–370.
    72. Woo, T.; Adachi, J.D. Role of bisphosphonates and calcitonin in the prevention and treatment of osteoporosis. Best Pract. Res. Clin. Rheumatol. 2001, 15, 469–481.