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

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Abstract:

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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Tables

Generic image for table
TABLE 1

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
Generic image for table
TABLE 2

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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