Chapter 9 : The Potential of Probiotics as a Therapy for Osteoporosis

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The adult human skeleton comprises 206 bones, excluding the sesamoid bones ( ). The bones are subdivided into four general types: long bones, short bones, flat bones, and irregular bones. Long bones such as the femur are composed of a hollow diaphysis which flares at the end to form the metaphysis, the region below the growth plate, and the epiphysis, the region above the growth plate. The diaphysis, also known as the shaft, is mainly composed of dense, solid bone known as cortical bone, whereas the metaphysis and epiphysis contain a honeycomb-like network of interconnected trabecular plates surrounding bone marrow known as cancellous or trabecular bone ( ).

Citation: Collins F, Rios-Arce N, Schepper J, Parameswaran N, McCabe L. 2018. The Potential of Probiotics as a Therapy for Osteoporosis, p 213-233. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0015-2016
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Figure 1

A simplified representation of the bone remodeling cycle. The initiation phase of bone remodeling is induced by mechanical strain, damage, or signals from cytokines or systemic factors. This generates local signals that lead to the bone-lining cells separating from the bone surface and forming a canopy over the site to be resorbed ( ). Osteoclasts and their precursors are then recruited to the site of bone remodeling from the circulatory system via capillaries that are closely associated with the bone remodeling compartment ( ). The signals for the initiation of osteoclast differentiation and resorption, macrophage colony stimulating factor and receptor activator of NF-κB ligand, are provided by cells of the osteoblast lineage, including osteocytes as well as T and B cells ( ). Once the remodeling process is initiated, resorption of the bone occurs. Osteoclasts attach to the exposed surface of the mineralized matrix, where they polarize and form a sealed microenvironment. This sealed microenvironment is then acidified to break down the inorganic component of bone followed by release of the enzymes cathepsin K, matrix metalloproteinase-9 (MMP-9), and tartrate-resistant acid phosphatase, which break down the organic component ( ). Following resorption of the old damaged bone, the process undergoes reversal. Toward the end of the resorption phase of the bone remodeling cycle, mononuclear cells of the osteoblast lineage move into the resorption pit. These mononuclear cells remove the old demineralized collagen while laying down a new thin layer ( ). During this phase the process of “coupling” bone resorption to bone formation occurs to ensure that the volume of bone removed is replaced. Coupling of bone resorption to bone formation is a multifaceted process with numerous regulator molecules derived from the matrix, secreted by cells, or membrane-bound contributing to the process ( ). Bone formation is a two-step process and proceeds slowly, taking approximately 3 months (compared to resorption, which typically takes 3 weeks). The osteoblast first secretes the unmineralized osteoid, which is then mineralized through the incorporation of hydroxyapatite ( ). When the osteoblasts have completed the matrix formation, they undergo a number of possible fates. The majority of osteoblasts become apoptotic; however, some get trapped in the mineralized matrix and undergo further differentiation into the osteocyte, while others may become inactive bone-lining cells ( ). Through the production of sclerostin, an inhibitor of Wnt signaling, the osteocyte can regulate the amount of new bone formation that takes place ( ).

Citation: Collins F, Rios-Arce N, Schepper J, Parameswaran N, McCabe L. 2018. The Potential of Probiotics as a Therapy for Osteoporosis, p 213-233. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0015-2016
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Figure 2

Osteoclast differentiation is the process by which mononuclear cells undergo fusion into the multinucleated osteoclast. Three cytokines are critical for osteoclast differentiation: MCSF, RANKL, and OPG, a soluble decoy receptor for RANKL ( ). In the initial stages of differentiation, precursor cells proliferate in response to MCSF signaling through its receptor c-FMS ( ). RANKL, expressed as a membrane-bound or soluble form, then binds to its receptor, RANK, which is present on the precursor cells ( ). This results in the transcription and activation of numerous osteoclast-specific genes: cathepsin K, tartrate-resistant acid phosphatase (an osteoclast marker), calcitonin receptor, and B3 integrin ( ). The precursor cells then migrate along chemokine gradients and fuse together to form the multinucleated osteoclast. Control of osteoclast differentiation is via the soluble receptor OPG, which competes with RANK for RANKL binding, thus inhibiting osteoclast differentiation ( ). Abbreviations: MCSF, macrophage colony stimulating factor; RANK(L), receptor activator of NF-κB (ligand); OPG, osteoprotegerin.

Citation: Collins F, Rios-Arce N, Schepper J, Parameswaran N, McCabe L. 2018. The Potential of Probiotics as a Therapy for Osteoporosis, p 213-233. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0015-2016
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Figure 3

Osteoblast differentiation. Signaling by members of the canonical Wnt/β-catenin pathway such as Wnt10b, BMP2, and BMP4 directs the mesenchymal stem cell fate toward the osteoblast lineage. This is achieved by suppressing the adipogenic transcription factors C/EBPα and PPARγ while inducing the osteogenic transcription factors Runx2 and osterix ( ). This immature osteoblast still has the potential to divide and express low levels of alkaline phosphatase activity, as well as to synthesize type I collagen, which makes up to 90% of the organic component of bone ( ). Differentiation to the nonproliferating mature cuboidal osteoblast that actively mineralizes bone matrix is dependent on the transcription factor osterix ( ). Before the newly laid matrix can be mineralized, however, it must first undergo maturation. Matrix maturation is associated with increased expression of alkaline phosphatase and several noncollagen proteins, including osteocalcin, osteopontin, and bone sialoprotein ( ). Mineralization of bone is completed by the incorporation of hydroxyapatite [Ca(PO)(OH)] into the newly deposited osteoid. Membrane-bound extracellular bodies (extracellular matrix vesicles) released from the osteoblast facilitate initial mineral deposition by accumulating calcium and phosphate ions in a protected environment. Clusters of these ions come together to form the first stable crystals. Addition of ions to these crystals follows, resulting in their growth ( ). At the completion of bone formation, a subset of osteoblasts can undergo further differentiation, upon being entombed in the bone matrix, and become osteocytes. The remaining osteoblasts are thought to either undergo apoptosis or become inactive bone-lining cells ( ).

Citation: Collins F, Rios-Arce N, Schepper J, Parameswaran N, McCabe L. 2018. The Potential of Probiotics as a Therapy for Osteoporosis, p 213-233. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0015-2016
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Figure 4

Cross-talk between osteoclasts, osteoblasts, and the immune system. Activated T lymphocytes, specifically T helper 17 cells, have been identified as osteoclastogenic through the expression of RANKL and the cytokine interleukin (IL)-17, which induces RANKL expression on osteoblasts ( ). Furthermore, expression of IL-17 enhances local inflammation, driving expression of other proinflammatory cytokines and promoting additional RANKL expression ( ). In addition to IL-17, T cell TNFα production has been demonstrated to affect the balance of bone remodeling. Increased T cell TNFα enhances osteoclastogenesis while inhibiting osteoblast differentiation and collagen synthesis ( ). In addition to pro-osteoclastogenic cytokines, T-lymphocytes also secrete IL-10, IL-4, and interferon (IFN)-γ that are potentially antiosteoclastogenic ( ). A role for B-lymphocytes in bone homeostasis has been suggested because B cell-deficient mice exhibit an osteoporotic phenotype ( ). B-lymphocytes are responsible for 64% of total bone marrow OPG production, with 45% of this derived from mature B cells ( ).

Citation: Collins F, Rios-Arce N, Schepper J, Parameswaran N, McCabe L. 2018. The Potential of Probiotics as a Therapy for Osteoporosis, p 213-233. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0015-2016
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Figure 5

Potential mechanism by which probiotic bacteria benefit bone. (a) Probiotic bacteria or their secreted factors interact with the intestinal epithelial barrier and cells in the lamina propria. Within the lamina propria the probiotic bacteria/secreted factors interact with antigen-presenting cells such dendritic cells, modulating their immune response. This results in a reduction of inflammatory cytokines, leading to an uptake in minerals from the intestinal lumen. (b) The bacterial secreted factors then pass into the bloodstream and are transported to the bone. Here they can interact with osteoclasts and osteoblasts as well as immune cells. This could then reduce expression of proinflammatory and pro-osteoclastogenic cytokines and oxidative stress while enhancing mineral apposition and Wnt10b expression. This modulation results in reduced osteoclast formation, subsequently leading to increased levels of bone.

Citation: Collins F, Rios-Arce N, Schepper J, Parameswaran N, McCabe L. 2018. The Potential of Probiotics as a Therapy for Osteoporosis, p 213-233. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0015-2016
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1. Rizzo DC . 2015. Fundamentals of Anatomy and Physiology. Cengage Learning, Boston, MA.[PubMed]
2. Turner RT,, Kalra SP,, Wong CP,, Philbrick KA,, Lindenmaier LB,, Boghossian S,, Iwaniec UT . 2013. Peripheral leptin regulates bone formation. J Bone Miner Res 28 : 22 34.[CrossRef] [PubMed]
3. Wong IPL,, Driessler F,, Khor EC,, Shi YC,, Hörmer B,, Nguyen AD,, Enriquez RF,, Eisman JA,, Sainsbury A,, Herzog H,, Baldock PA . 2012. Peptide YY regulates bone remodeling in mice: a link between gut and skeletal biology. PLoS One 7 : e40038.[CrossRef]
4. Takayanagi H . 2009. Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol 5 : 667 676.[CrossRef] [PubMed]
5. Hauge EM,, Qvesel D,, Eriksen EF,, Mosekilde L,, Melsen F . 2001. Cancellous bone remodeling occurs in specialized compartments lined by cells expressing osteoblastic markers. J Bone Miner Res 16 : 1575 1582.[CrossRef] [PubMed]
6. Karsenty G,, Kronenberg HM,, Settembre C . 2009. Genetic control of bone formation. Annu Rev Cell Dev Biol 25 : 629 648.[CrossRef] [PubMed]
7. Teitelbaum SL . 2007. Osteoclasts: what do they do and how do they do it? Am J Pathol 170 : 427 435.[CrossRef] [PubMed]
8. Bonewald LF,, Johnson ML . 2008. Osteocytes, mechanosensing and Wnt signaling. Bone 42 : 606 615.[CrossRef] [PubMed]
9. Andersen TL,, Sondergaard TE,, Skorzynska KE,, Dagnaes-Hansen F,, Plesner TL,, Hauge EM,, Plesner T,, Delaisse JM . 2009. A physical mechanism for coupling bone resorption and formation in adult human bone. Am J Pathol 174 : 239 247.[CrossRef] [PubMed]
10. Xing L,, Schwarz EM,, Boyce BF . 2005. Osteoclast precursors, RANKL/RANK, and immunology. Immunol Rev 208 : 19 29.[CrossRef] [PubMed]
11. Pittenger MF,, Mackay AM,, Beck SC,, Jaiswal RK,, Douglas R,, Mosca JD , , et al . 2013. Multilineage potential of adult human mesenchymal stem cells. Science 284 : 143 147.
12. Takayanagi H . 2010. New immune connections in osteoclast formation. Ann N Y Acad Sci 1192 : 117 123.[CrossRef] [PubMed]
13. Long F . 2011. Building strong bones: molecular regulation of the osteoblast lineage. Nat Rev Mol Cell Biol 13 : 27 38.[CrossRef] [PubMed]
14. Matsuo K,, Irie N . 2008. Osteoclast-osteoblast communication. Arch Biochem Biophys 473 : 201 209.[CrossRef] [PubMed]
15. Am J Med . 1993. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 94 : 646650.[CrossRef] [PubMed]
16. International Osteoporosis Foundation . 2015. Facts and Statistics. https://www.iofbonehealth.org/facts-statistics.
17. Burge R,, Dawson-Hughes B,, Solomon DH,, Wong JB,, King A,, Tosteson A . 2007. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res 22 : 465 475.[CrossRef] [PubMed]
18. Manolagas SC . 2010. From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr Rev 31 : 266 300.[CrossRef] [PubMed]
19. Pfeilschifter J,, Köditz R,, Pfohl M,, Schatz H . 2002. Changes in proinflammatory cytokine activity after menopause. Endocr Rev 23 : 90 119.[CrossRef] [PubMed]
20. Bismar H,, Diel I,, Ziegler R,, Pfeilschifter J . 1995. Increased cytokine secretion by human bone marrow cells after menopause or discontinuation of estrogen replacement. J Clin Endocrinol Metab 80 : 3351 3355.[PubMed]
21. D’Amelio P,, Grimaldi A,, Di Bella S,, Brianza SZ,, Cristofaro MA,, Tamone C,, Giribaldi G,, Ulliers D,, Pescarmona GP,, Isaia G . 2008. Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: a key mechanism in osteoporosis. Bone 43 : 92 100.[CrossRef] [PubMed]
22. Weitzmann MN,, Roggia C,, Toraldo G,, Weitzmann L,, Pacifici R . 2002. Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency. J Clin Invest 110 : 1643 1650.[CrossRef] [PubMed]
23. Eghbali-Fatourechi G,, Khosla S,, Sanyal A,, Boyle WJ,, Lacey DL,, Riggs BL . 2003. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest 111 : 1221 1230.[CrossRef] [PubMed]
24. Cenci S,, Weitzmann MN,, Roggia C,, Namba N,, Novack D,, Woodring J,, Pacifici R . 2000. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest 106 : 1229 1237.[CrossRef] [PubMed]
25. Li JY,, Tawfeek H,, Bedi B,, Yang X,, Adams J,, Gao KY,, Zayzafoon M,, Weitzmann MN,, Pacifici R . 2011. Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand. Proc Natl Acad Sci USA 108 : 768 773.[CrossRef] [PubMed]
26. Kim BJ,, Bae SJ,, Lee SY,, Lee YS,, Baek JE,, Park SY,, Lee SH,, Koh JM,, Kim GS . 2012. TNF-α mediates the stimulation of sclerostin expression in an estrogen-deficient condition. Biochem Biophys Res Commun 424 : 170 175.[CrossRef] [PubMed]
27. Foo C,, Frey S,, Yang HH,, Zellweger R,, Filgueira L . 2007. Downregulation of beta-catenin and transdifferentiation of human osteoblasts to adipocytes under estrogen deficiency. Gynecol Endocrinol 23 : 535 540.[CrossRef] [PubMed]
28. Bennett CN,, Longo KA,, Wright WS,, Suva LJ,, Lane TF,, Hankenson KD,, MacDougald OA . 2005. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci USA 102 : 3324 3329.[CrossRef] [PubMed]
29. García-Moreno C,, Catalán MP,, Ortiz A,, Alvarez L,, De la Piedra C . 2004. Modulation of survival in osteoblasts from postmenopausal women. Bone 35 : 170 177.[CrossRef] [PubMed]
30. Kovacic N,, Grcevic D,, Katavic V,, Lukic IK,, Grubisic V,, Mihovilovic K,, Cvija H,, Croucher PI,, Marusic A . 2010. Fas receptor is required for estrogen deficiency-induced bone loss in mice. Lab Invest 90 : 402 413.[CrossRef] [PubMed]
31. Fitzpatrick LA . 2002. Secondary causes of osteoporosis. Mayo Clin Proc 77 : 453 468.[CrossRef] [PubMed]
32. Painter SE,, Kleerekoper M,, Camacho PM . 2006. Secondary osteoporosis: a review of the recent evidence. Endocr Pract 12 : 436 445.[CrossRef] [PubMed]
33. Ghishan FK,, Kiela PR . 2011. Advances in the understanding of mineral and bone metabolism in inflammatory bowel diseases. Am J Physiol Gastrointest Liver Physiol 300 : G191 G201.[CrossRef] [PubMed]
34. Levin ME,, Boisseau VC,, Avioli LV . 1976. Effects of diabetes mellitus on bone mass in juvenile and adult-onset diabetes. N Engl J Med 294 : 241 245.[CrossRef] [PubMed]
35. Coe LM,, Zhang J,, McCabe LR . 2013. Both spontaneous Ins2(+/−) and streptozotocin-induced type I diabetes cause bone loss in young mice. J Cell Physiol 228 : 689 695.[CrossRef] [PubMed]
36. Coe LM,, Irwin R,, Lippner D,, McCabe LR . 2011. The bone marrow microenvironment contributes to type I diabetes induced osteoblast death. J Cell Physiol 226 : 477 483.[CrossRef] [PubMed]
37. Motyl KJ,, Botolin S,, Irwin R,, Appledorn DM,, Kadakia T,, Amalfitano A,, Schwartz RC,, McCabe LR . 2009. Bone inflammation and altered gene expression with type I diabetes early onset. J Cell Physiol 218 : 575 583.[CrossRef] [PubMed]
38. Zhang J,, Motyl KJ,, Irwin R,, MacDougald OA,, Britton RA,, McCabe LR . 2015. Loss of bone and Wnt10b expression in male type 1 diabetic mice is blocked by the probiotic L. reuteri . Endocrinology 156 : 3169 3182.[PubMed]
39. Kanis JA,, McCloskey EV,, Johansson H,, Cooper C,, Rizzoli R,, Reginster JY , Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO), Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF) . 2013. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 24 : 23 57.[CrossRef] [PubMed]
40. Papapoulos SE . 2008. Bisphosphonates: how do they work? Best Pract Res Clin Endocrinol Metab 22 : 831 847.[CrossRef] [PubMed]
41. Reid IR . 2015. Efficacy, effectiveness and side effects of medications used to prevent fractures. J Intern Med 277 : 690 706.[CrossRef] [PubMed]
42. Sambrook P,, Cooper C . 2006. Osteoporosis. Lancet 367 : 2010 2018.[CrossRef] [PubMed]
43. Jones RM,, Mulle JG,, Pacifici R . 2017. Osteomicrobiology: the influence of gut microbiota on bone in health and disease. Bone. [Epub ahead of print.][CrossRef] [PubMed]
44. Ohlsson C,, Sjögren K . 2015. Effects of the gut microbiota on bone mass. Trends Endocrinol Metab 26 : 69 74.[CrossRef] [PubMed]
45. McCabe L,, Britton RA,, Parameswaran N . 2015. Prebiotic and probiotic regulation of bone health: role of the intestine and its microbiome. Curr Osteoporos Rep 13 : 363 371.[CrossRef] [PubMed]
46. Loh G,, Blaut M . 2012. Role of commensal gut bacteria in inflammatory bowel diseases. Gut Microbes 3 : 544 555.[CrossRef] [PubMed]
47. Fukuda S,, Ohno H . 2014. Gut microbiome and metabolic diseases. Semin Immunopathol 36 : 103 114.[CrossRef] [PubMed]
48. Ley RE,, Turnbaugh PJ,, Klein S,, Gordon JI . 2006. Microbial ecology: human gut microbes associated with obesity. Nature 444 : 1022 1023.[CrossRef] [PubMed]
49. Baggio LL,, Drucker DJ . 2007. Biology of incretins: GLP-1 and GIP. Gastroenterology 132 : 2131 2157.[CrossRef] [PubMed]
50. Yadav VK,, Ryu JH,, Suda N,, Tanaka KF,, Gingrich JA,, Schütz G,, Glorieux FH,, Chiang CY,, Zajac JD,, Insogna KL,, Mann JJ,, Hen R,, Ducy P,, Karsenty G . 2008. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135 : 825 837.[CrossRef] [PubMed]
51. Sjögren K,, Engdahl C,, Henning P,, Lerner UH,, Tremaroli V,, Lagerquist MK,, Bäckhed F,, Ohlsson C . 2012. The gut microbiota regulates bone mass in mice. J Bone Miner Res 27 : 1357 1367.[CrossRef] [PubMed]
52. Li J-Y,, Chassaing B,, Tyagi AM,, Vaccaro C,, Luo T,, Adams J,, Darby TM,, Weitzmann MN,, Mulle JG,, Gewirtz AT,, Jones RM,, Pacifici R . 2016. Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics. J Clin Invest 126 : 2049 2063.[CrossRef] [PubMed]
53. Yan J,, Herzog JW,, Tsang K,, Brennan CA,, Bower MA,, Garrett WS,, Sartor BR,, Aliprantis AO,, Charles JF . 2016. Gut microbiota induce IGF-1 and promote bone formation and growth. Proc Natl Acad Sci USA 113 : E7554 E7563.[CrossRef] [PubMed]
54. Araya M,, Morelli L,, Reid G,, Sanders ME,, Stanton C . 2002. Guidelines for the Evaluation of Probiotics in Food. FAO/WHO, London, Ontario, Canada.
55. Czerucka D,, Piche T,, Rampal P . 2007. Review article: yeast as probiotics: Saccharomyces boulardii . Aliment Pharmacol Ther 26 : 767 778.[CrossRef] [PubMed]
56. FAO and WHO . 2006. Probiotics in Food. Food and Nutrition Paper 85. FAO/WHO, Rome, Italy.
57. Broekaert IJ,, Nanthakumar NN,, Walker WA . 2007. Secreted probiotic factors ameliorate enteropathogenic infection in zinc-deficient human Caco-2 and T84 cell lines. Pediatr Res 62 : 139 144.[CrossRef] [PubMed]
58. Matsuguchi T,, Takagi A,, Matsuzaki T,, Nagaoka M,, Ishikawa K,, Yokokura T,, Yoshikai Y . 2003. Lipoteichoic acids from Lactobacillus strains elicit strong tumor necrosis factor alpha-inducing activities in macrophages through Toll-like receptor 2. Clin Diagn Lab Immunol 10 : 259 266.
59. Nishimura J . 2014. Exopolysaccharides produced from Lactobacillus delbrueckii subsp. bulgaricus . Adv Microbiol 4 : 1017 1023.[CrossRef]
60. Sougioultzis S,, Simeonidis S,, Bhaskar KR,, Chen X,, Anton PM,, Keates S,, Pothoulakis C,, Kelly CP . 2006. Saccharomyces boulardii produces a soluble anti-inflammatory factor that inhibits NF-kappaB-mediated IL-8 gene expression. Biochem Biophys Res Commun 343 : 69 76.[CrossRef] [PubMed]
61. McCabe LR,, Irwin R,, Schaefer L,, Britton RA . 2013. Probiotic use decreases intestinal inflammation and increases bone density in healthy male but not female mice. J Cell Physiol 228 : 1793 1798.[CrossRef] [PubMed]
62. Collins FL,, Irwin R,, Bierhalter H,, Schepper J,, Britton RA,, Parameswaran N,, McCabe LR . 2016. Lactobacillus reuteri 6475 increases bone density in intact females only under an inflammatory setting. PLoS One 11 : e0153180.[CrossRef] [PubMed]
63. Ghanem KZ,, Badawy IH,, Abdel-Salam AM . 2004. Influence of yoghurt and probiotic yoghurt on the absorption of calcium, magnesium, iron and bone mineralization in rats. Milchwissenschaft 59 : 472 475.
64. Kruger MC,, Fear A,, Chua W-H,, Plimmer GG,, Schollum LM . 2009. The effect of Lactobacillus rhamnosus HN001 on mineral absorption and bone health in growing male and ovariectomised female rats. Dairy Sci Technol 89 : 219 231.[CrossRef]
65. Rodrigues FC,, Castro AS,, Rodrigues VC,, Fernandes SA,, Fontes EA,, de Oliveira TT,, Martino HS,, de Luces Fortes Ferreira CL . 2012. Yacon flour and Bifidobacterium longum modulate bone health in rats. J Med Food 15 : 664 670.[CrossRef] [PubMed]
66. Tomofuji T,, Ekuni D,, Azuma T,, Irie K,, Endo Y,, Yamamoto T,, Ishikado A,, Sato T,, Harada K,, Suido H,, Morita M . 2012. Supplementation of broccoli or Bifidobacterium longum-fermented broccoli suppresses serum lipid peroxidation and osteoclast differentiation on alveolar bone surface in rats fed a high-cholesterol diet. Nutr Res 32 : 301 307.[CrossRef] [PubMed]
67. Britton RA,, Irwin R,, Quach D,, Schaefer L,, Zhang J,, Lee T,, Parameswaran N,, McCabe LR . 2014. Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J Cell Physiol 229 : 1822 1830.[CrossRef] [PubMed]
68. Ohlsson C,, Engdahl C,, Fåk F,, Andersson A,, Windahl SH,, Farman HH,, Movérare-Skrtic S,, Islander U,, Sjögren K . 2014. Probiotics protect mice from ovariectomy-induced cortical bone loss. PLoS One 9 : e92368.[CrossRef] [PubMed]
69. Chiang SS,, Pan TM . 2011. Antiosteoporotic effects of Lactobacillus-fermented soy skim milk on bone mineral density and the microstructure of femoral bone in ovariectomized mice. J Agric Food Chem 59 : 7734 7742.[CrossRef] [PubMed]
70. Caballero-Franco C,, Keller K,, De Simone C,, Chadee K . 2007. The VSL#3 probiotic formula induces mucin gene expression and secretion in colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol 292 : G315 G322.[CrossRef] [PubMed]
71. Parvaneh K,, Ebrahimi M,, Sabran MR,, Karimi G,, Hwei ANM,, Abdul-Majeed S , , et al . 2015. Probiotics ( Bifidobacterium longum) increase bone mass density and upregulate Sparc and Bmp-2 genes in rats with bone loss resulting from ovariectomy. Biomed Res Int 2015 : 1 10.[PubMed]
72. McCabe L,, Zhang J,, Raehtz S . 2011. Understanding the skeletal pathology of type 1 and 2 diabetes mellitus. Crit Rev Eukaryot Gene Expr 21 : 187 206.[CrossRef] [PubMed]
73. Payne JM . 1977. Metabolic Diseases in Farm Animals. Butterworth-Heinemann, London, United Kingdom.
74. Sullivan TW . 1994. Skeletal problems in poultry: estimated annual cost and descriptions. Poult Sci 73 : 879 882.[CrossRef] [PubMed]
75. Nahashon SN,, Nakaue HS,, Mirosh LW . 1994. Production variables and nutrient retention in single comb white Leghorn laying pullets fed diets supplemented with direct-fed microbials. Poult Sci 73 : 1699 1711.[CrossRef] [PubMed]
76. Jin LZ,, Ho YW,, Abdullah N,, Jalaludin S . 1997. Probiotics in poultry: modes of action. Worlds Poult Sci J 53 : 351 368.
77. Nava GM,, Bielke LR,, Callaway TR,, Castañeda MP . 2005. Probiotic alternatives to reduce gastrointestinal infections: the poultry experience. Anim Health Res Rev 6 : 105 118.[CrossRef] [PubMed]
78. Khan RU,, Naz S . 2013. The applications of probiotics in poultry production. Worlds Poult Sci J 69 : 621 632.[CrossRef]
79. Mutuş R,, Kocabagli N,, Alp M,, Acar N,, Eren M,, Gezen SS . 2006. The effect of dietary probiotic supplementation on tibial bone characteristics and strength in broilers. Poult Sci 85 : 1621 1625.[PubMed]
80. Plavnik I,, Scott ML . 1980. Effects of additional vitamins, minerals, or brewer’s yeast upon leg weaknesses in broiler chickens. Poult Sci 59 : 459 464.[CrossRef] [PubMed]
81. Thomas CM,, Hong T,, van Pijkeren JP,, Hemarajata P,, Trinh DV,, Hu W,, Britton RA,, Kalkum M,, Versalovic J . 2012. Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling. PLoS One 7 : e31951.[CrossRef] [PubMed]
82. Kim JG,, Lee E,, Kim SH,, Whang KY,, Oh S,, Imm JY . 2009. Effects of a Lactobacillus casei 393 fermented milk product on bone metabolism in ovariectomised rats. Int Dairy J 19 : 690 695.[CrossRef]
83. Narva M,, Halleen J,, Väänänen K,, Korpela R . 2004. Effects of Lactobacillus helveticus fermented milk on bone cells in vitro . Life Sci 75 : 1727 1734.[CrossRef] [PubMed]
84. Crittenden RG,, Martinez NR,, Playne MJ . 2003. Synthesis and utilisation of folate by yoghurt starter cultures and probiotic bacteria. Int J Food Microbiol 80 : 217 222.[CrossRef] [PubMed]
85. Arunachalam KD . 1999. Role of bifidobacteria in nutrition, medicine and technology. Nutr Res 19 : 1559 1597.[CrossRef]
86. Campbell JM,, Fahey GC Jr,, Wolf BW . 1997. Selected indigestible oligosaccharides affect large bowel mass, cecal and fecal short-chain fatty acids, pH and microflora in rats. J Nutr 127 : 130 136.[PubMed]
87. Narva M,, Collin M,, Lamberg-Allardt C,, Kärkkäinen M,, Poussa T,, Vapaatalo H,, Korpela R . 2004. Effects of long-term intervention with Lactobacillus helveticus-fermented milk on bone mineral density and bone mineral content in growing rats. Ann Nutr Metab 48 : 228 234.[CrossRef] [PubMed]
88. Bai XC,, Lu D,, Bai J,, Zheng H,, Ke ZY,, Li XM,, Luo SQ . 2004. Oxidative stress inhibits osteoblastic differentiation of bone cells by ERK and NF-kappaB. Biochem Biophys Res Commun 314 : 197 207.[CrossRef] [PubMed]
89. Suda N,, Morita I,, Kuroda T,, Murota S . 1993. Participation of oxidative stress in the process of osteoclast differentiation. Biochim Biophys Acta 1157 : 318 323.[CrossRef]
90. Sims NA,, Martin TJ . 2014. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. Bonekey Rep 3 : 481.[PubMed]
91. Kristensen HB,, Andersen TL,, Marcussen N,, Rolighed L,, Delaisse JM . 2013. Increased presence of capillaries next to remodeling sites in adult human cancellous bone. J Bone Miner Res 28 : 574 585.[CrossRef] [PubMed]
92. Nakashima T,, Hayashi M,, Fukunaga T,, Kurata K,, Oh-Hora M,, Feng JQ,, Bonewald LF,, Kodama T,, Wutz A,, Wagner EF,, Penninger JM,, Takayanagi H . 2011. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 17 : 1231 1234.[CrossRef] [PubMed]
93. Fuller K,, Wong B,, Fox S,, Choi Y,, Chambers TJ . 1998. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med 188 : 997 1001.[CrossRef] [PubMed]
94. Yoshida H,, Hayashi S,, Kunisada T,, Ogawa M,, Nishikawa S,, Okamura H,, Sudo T,, Shultz LD,, Nishikawa S . 1990. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345 : 442 444.[CrossRef] [PubMed]
95. Teitelbaum SL . 2000. Bone resorption by osteoclasts. Science 289 : 1504 1508.[CrossRef] [PubMed]
96. Everts V,, Delaissé JM,, Korper W,, Jansen DC,, Tigchelaar-Gutter W,, Saftig P,, Beertsen W . 2002. The bone lining cell: its role in cleaning Howship’s lacunae and initiating bone formation. J Bone Miner Res 17 : 77 90.[CrossRef] [PubMed]
97. Edwards CM,, Mundy GR . 2008. Eph receptors and ephrin signaling pathways: a role in bone homeostasis. Int J Med Sci 5 : 263 272.[CrossRef] [PubMed]
98. Tang Y,, Wu X,, Lei W,, Pang L,, Wan C,, Shi Z,, Zhao L,, Nagy TR,, Peng X,, Hu J,, Feng X,, Van Hul W,, Wan M,, Cao X . 2009. TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med 15 : 757 765.[CrossRef] [PubMed]
99. Anderson HC . 2003. Matrix vesicles and calcification. Curr Rheumatol Rep 5 : 222 226.[CrossRef] [PubMed]
100. Bonewald LF . 2011. The amazing osteocyte. J Bone Miner Res 26 : 229 238.[CrossRef] [PubMed]
101. Tanaka S,, Takahashi N,, Udagawa N,, Tamura T,, Akatsu T,, Stanley ER,, Kurokawa T,, Suda T . 1993. Macrophage colony-stimulating factor is indispensable for both proliferation and differentiation of osteoclast progenitors. J Clin Invest 91 : 257 263.[CrossRef] [PubMed]
102. Lacey DL,, Timms E,, Tan HL,, Kelley MJ,, Dunstan CR,, Burgess T,, Elliott R,, Colombero A,, Elliott G,, Scully S,, Hsu H,, Sullivan J,, Hawkins N,, Davy E,, Capparelli C,, Eli A,, Qian YX,, Kaufman S,, Sarosi I,, Shalhoub V,, Senaldi G,, Guo J,, Delaney J,, Boyle WJ . 1998. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93 : 165 176.[CrossRef]
103. Kong YY,, Yoshida H,, Sarosi I,, Tan HL,, Timms E,, Capparelli C,, Morony S,, Oliveira-dos-Santos AJ,, Van G,, Itie A,, Khoo W,, Wakeham A,, Dunstan CR,, Lacey DL,, Mak TW,, Boyle WJ,, Penninger JM . 1999. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397 : 315 323.[CrossRef] [PubMed]
104. Simonet WS,, Lacey DL,, Dunstan CR,, Kelley M,, Chang MS,, Lüthy R,, Nguyen HQ,, Wooden S,, Bennett L,, Boone T,, Shimamoto G,, DeRose M,, Elliott R,, Colombero A,, Tan HL,, Trail G,, Sullivan J,, Davy E,, Bucay N,, Renshaw-Gegg L,, Hughes TM,, Hill D,, Pattison W,, Campbell P,, Sander S,, Van G,, Tarpley J,, Derby P,, Lee R,, Boyle WJ . 1997. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89 : 309 319.[CrossRef] [PubMed]
105. Dai X-M,, Ryan GR,, Hapel AJ,, Dominguez MG,, Russell RG,, Kapp S,, Sylvestre V,, Stanley ER . 2002. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 99 : 111 120.[CrossRef] [PubMed]
106. Hsu H,, Lacey DL,, Dunstan CR,, Solovyev I,, Colombero A,, Timms E,, Tan HL,, Elliott G,, Kelley MJ,, Sarosi I,, Wang L,, Xia XZ,, Elliott R,, Chiu L,, Black T,, Scully S,, Capparelli C,, Morony S,, Shimamoto G,, Bass MB,, Boyle WJ . 1999. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 96 : 3540 3545.[CrossRef] [PubMed]
107. Dougall WC,, Glaccum M,, Charrier K,, Rohrbach K,, Brasel K,, De Smedt T,, Daro E,, Smith J,, Tometsko ME,, Maliszewski CR,, Armstrong A,, Shen V,, Bain S,, Cosman D,, Anderson D,, Morrissey PJ,, Peschon JJ,, Schuh J . 1999. RANK is essential for osteoclast and lymph node development. Genes Dev 13 : 2412 2424.[CrossRef] [PubMed]
108. Asagiri M,, Takayanagi H . 2007. The molecular understanding of osteoclast differentiation. Bone 40 : 251 264.[CrossRef] [PubMed]
109. Udagawa N,, Takahashi N,, Yasuda H,, Mizuno A,, Itoh K,, Ueno Y,, Shinki T,, Gillespie MT,, Martin TJ,, Higashio K,, Suda T . 2000. Osteoprotegerin produced by osteoblasts is an important regulator in osteoclast development and function. Endocrinology 141 : 3478 3484.[CrossRef] [PubMed]
110. Li Y,, Toraldo G,, Li A,, Yang X,, Zhang H,, Qian WP,, Weitzmann MN . 2007. B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo . Blood 109 : 3839 3848.[CrossRef] [PubMed]
111. Ducy P,, Zhang R,, Geoffroy V,, Ridall AL,, Karsenty G . 1997. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89 : 747 754.[CrossRef] [PubMed]
112. Nakashima K,, Zhou X,, Kunkel G,, Zhang Z,, Deng JM,, Behringer RR,, de Crombrugghe B . 2002. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108 : 17 29.[CrossRef] [PubMed]
113. Boskey AL . 2013. Bone composition: relationship to bone fragility and antiosteoporotic drug effects. Bonekey Rep 2 : 447.[CrossRef] [PubMed]
114. Yang X,, Matsuda K,, Bialek P,, Jacquot S,, Masuoka HC,, Schinke T,, Li L,, Brancorsini S,, Sassone-Corsi P,, Townes TM,, Hanauer A,, Karsenty G . 2004. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology: implication for Coffin-Lowry syndrome. Cell 117 : 387 398.[CrossRef]
115. Clarke B . 2008. Normal bone anatomy and physiology. Clin J Am Soc Nephrol 3( Suppl 3) : S131 S139.[CrossRef] [PubMed]
116. Robey P,, Boskey A, . 2006. Extracellular matrix and biomineralization of bone, p 12 19. In Favus MJ (ed), Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 6th ed. American Society for Bone and Mineral Research, Washington, DC.
117. Sato K,, Suematsu A,, Okamoto K,, Yamaguchi A,, Morishita Y,, Kadono Y,, Tanaka S,, Kodama T,, Akira S,, Iwakura Y,, Cua DJ,, Takayanagi H . 2006. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 203 : 2673 2682.[CrossRef] [PubMed]
118. Gilbert L,, He X,, Farmer P,, Boden S,, Kozlowski M,, Rubin J,, Nanes MS . 2000. Inhibition of osteoblast differentiation by tumor necrosis factor-alpha. Endocrinology 141 : 3956 3964.[CrossRef] [PubMed]
119. Centrella M,, McCarthy TL,, Canalis E . 1988. Tumor necrosis factor-alpha inhibits collagen synthesis and alkaline phosphatase activity independently of its effect on deoxyribonucleic acid synthesis in osteoblast-enriched bone cell cultures. Endocrinology 123 : 1442 1448.[CrossRef] [PubMed]
120. Takayanagi H,, Ogasawara K,, Hida S,, Chiba T,, Murata S,, Sato K,, Takaoka A,, Yokochi T,, Oda H,, Tanaka K,, Nakamura K,, Taniguchi T . 2000. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature 408 : 600 605.[CrossRef] [PubMed]
121. Eastell R . 2005. Osteoporosis. Medicine (Baltimore) 33 : 61 65.
122. Khosla S,, Amin S,, Orwoll E . 2008. Osteoporosis in men. Endocr Rev 29 : 441 464.[CrossRef] [PubMed]
123. Amdekar S,, Kumar A,, Sharma P,, Singh R,, Singh V . 2012. Lactobacillus protected bone damage and maintained the antioxidant status of liver and kidney homogenates in female wistar rats. Mol Cell Biochem 368 : 155 165.[CrossRef] [PubMed]
124. Rovenský J,, Svík K,, Matha V,, Istok R,, Ebringer L,, Ferencík M,, Stancíková M . 2004. The effects of Enterococcus faecium and selenium on methotrexate treatment in rat adjuvant-induced arthritis. Clin Dev Immunol 11 : 267 273.[CrossRef] [PubMed]


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Established treatments for osteoporosis

Citation: Collins F, Rios-Arce N, Schepper J, Parameswaran N, McCabe L. 2018. The Potential of Probiotics as a Therapy for Osteoporosis, p 213-233. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0015-2016
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Effect of probiotics on bone (animal studies)

Citation: Collins F, Rios-Arce N, Schepper J, Parameswaran N, McCabe L. 2018. The Potential of Probiotics as a Therapy for Osteoporosis, p 213-233. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0015-2016

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