The Role of Macrophage in the Pathogenesis of Osteoporosis

Osteoporosis is a systemic disease with progressive bone loss. The bone loss is associated with an imbalance between bone resorption via osteoclasts and bone formation via osteoblasts. Other cells including T cells, B cells, macrophages, and osteocytes are also involved in the pathogenesis of osteoporosis. Different cytokines from activated macrophages can regulate or stimulate the development of osteoclastogenesis-associated bone loss. The fusion of macrophages can form multinucleated osteoclasts and, thus, cause bone resorption via the expression of IL-4 and IL-13. Different cytokines, endocrines, and chemokines are also expressed that may affect the presentation of macrophages in osteoporosis. Macrophages have an effect on bone formation during fracture-associated bone repair. However, activated macrophages may secrete proinflammatory cytokines that induce bone loss by osteoclastogenesis, and are associated with the activation of bone resorption. Targeting activated macrophages at an appropriate stage may help inhibit or slow the progression of bone loss in patients with osteoporosis.

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Free Fatty Acid Receptor 4 (GPR120) Stimulates Bone Formation and Suppresses Bone Resorption in the Presence of Elevated n-3 Fatty Acid Levels

Endocrinology ◽

10.1210/en.2015-1855 ◽

2016 ◽

Vol 157 (7) ◽

pp. 2621-2635 ◽

Cited By ~ 23

Author(s):

Seong Hee Ahn ◽

Sook-Young Park ◽

Ji-Eun Baek ◽

Su-Youn Lee ◽

Wook-Young Baek ◽

...

Keyword(s):

Fatty Acid ◽

Free Fatty Acid ◽

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

High Fat Diet ◽

Wild Type ◽

High Fat ◽

Free Fatty Acid Receptor

Free fatty acid receptor 4 (FFA4) has been reported to be a receptor for n-3 fatty acids (FAs). Although n-3 FAs are beneficial for bone health, a role of FFA4 in bone metabolism has been rarely investigated. We noted that FFA4 was more abundantly expressed in both mature osteoclasts and osteoblasts than their respective precursors and that it was activated by docosahexaenoic acid. FFA4 knockout (Ffar4−/−) and wild-type mice exhibited similar bone masses when fed a normal diet. Because fat-1 transgenic (fat-1Tg+) mice endogenously converting n-6 to n-3 FAs contain high n-3 FA levels, we crossed Ffar4−/− and fat-1Tg+ mice over two generations to generate four genotypes of mice littermates: Ffar4+/+;fat-1Tg−, Ffar4+/+;fat-1Tg+, Ffar4−/−;fat-1Tg−, and Ffar4−/−;fat-1Tg+. Female and male littermates were included in ovariectomy- and high-fat diet-induced bone loss models, respectively. Female fat-1Tg+ mice decreased bone loss after ovariectomy both by promoting osteoblastic bone formation and inhibiting osteoclastic bone resorption than their wild-type littermates, only when they had the Ffar4+/+ background, but not the Ffar4−/− background. In a high-fat diet-fed model, male fat-1Tg+ mice had higher bone mass resulting from stimulated bone formation and reduced bone resorption than their wild-type littermates, only when they had the Ffar4+/+ background, but not the Ffar4−/− background. In vitro studies supported the role of FFA4 as n-3 FA receptor in bone metabolism. In conclusion, FFA4 is a dual-acting factor that increases osteoblastic bone formation and decreases osteoclastic bone resorption, suggesting that it may be an ideal target for modulating metabolic bone diseases.

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Bone and the Immune System

Toxicologic Pathology ◽

10.1177/0192623317735316 ◽

2017 ◽

Vol 45 (7) ◽

pp. 911-924 ◽

Cited By ~ 44

Author(s):

M. Neale Weitzmann

Keyword(s):

T Cells ◽

Immune System ◽

T Cell ◽

B Cells ◽

Bone Resorption ◽

Bone Loss ◽

Fracture Risk ◽

Integration Site ◽

Therapeutic Interventions ◽

Activated T Cells

Osteoporosis increases fracture risk, a cause of crippling morbidity and mortality. The immunoskeletal interface (ISI) is a centralization of cell and cytokine effectors shared between skeletal and immune systems. Consequently, the immune system mediates powerful effects on bone turnover. Physiologically, B cells secrete osteoprotegerin (OPG), a potent anti-osteoclastogenic factor that preserves bone mass. However, activated T cells and B cells secrete pro-osteoclastogenic factors including receptor activator of Nuclear factor-kappaB (NF-kB) ligand (RANKL), Interleukin (IL)-17A, and tumor necrosis factor (TNF)-α promoting bone loss in inflammatory states such as rheumatoid arthritis. Recently, ISI disruption has been linked to osteoporosis in human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS), where elevated B cell RANKL and diminished OPG drive bone resorption. HIV-antiretroviral therapy paradoxically intensifies bone loss during disease reversal, as immune reconstitution produces osteoclastogenic cytokines. Interestingly, in estrogen deficiency, activated T cells secrete RANKL, TNF, and IL-17A that amplify bone resorption and contribute to postmenopausal osteoporosis. T cell–produced TNF and IL-17A further contribute to bone loss in hyperparathyroidism, while T cell production of the anabolic Wingless integration site (Wnt) ligand, Wnt10b, promotes bone formation in response to anabolic parathyroid hormone and the immunomodulatory costimulation inhibitor cytotoxic T lymphocyte–associated protein-4-IgG (abatacept). These findings provide a window into the workings of the ISI and suggest novel targets for future therapeutic interventions to reduce fracture risk.

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Cyclophosphamide immunosuppressed Xid mice model clarify the protective role of B cells in experimental encephalitozoonosis

10.1101/430256 ◽

2018 ◽

Author(s):

Carla Renata Serantoni Moysés ◽

Lidiana Flora Vidôto da Costa ◽

Elizabeth Cristina Perez ◽

José Guilherme Xavier ◽

Diva Denelle Spadacci-Morena ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

B Cells ◽

T Lymphocytes ◽

Proinflammatory Cytokines ◽

The Other ◽

Natural Resistance ◽

Encephalitozoon Cuniculi ◽

Deficient Mice

AbstractEncephalitozoon cuniculiis an intracellular pathogen that stablishes a balanced relationship with immunocompetent individuals, which is dependent of T lymphocytes activity. We previously showed X-linked immunodeficiency (XID – B cell deficient) mice are more susceptible to encephalitozoonosis and B-1 cells presence influences in the immune response. Because XID mice are deficient both in B-1 and B-2 cells, here we investigate the role of these cells againstE. cuniculiinfection using cyclophosphamide (Cy) immunosuppressed murine model to exacerbate the infection. XID mice presented lethargy and severe symptoms, associated with encephalitozoonosis and there was an increase in the peritoneal populations of CD8+and CD4+T lymphocytes and macrophages and also in the proinflammatory cytokines IFN-γ, TNF-α and IL-6. In BALB/c mice, no clinical signs were observed and there was an increase of T lymphocytes and macrophages in the spleen, showing an effective immune response. B-2 cells transfer to XID mice resulted in reduction of symptoms and lesion area with increase of B-2 and CD4+T populations in the spleen. B-1 cells transfer increased the peritoneal populations of B-2 cells and macrophages and also reduced the symptoms. Therefore, the immunodeficiency of B cells associated to Cy immunosuppression condition leads to disseminated and severe encephalitozoonosis in XID mice with absence of splenic immune response and ineffective local immune response, evidencing the B-1 and B-2 cells role against microsporidiosis.Author summaryThe adaptive immune response plays a key role againstEncephalitozoon cuniculi, an opportunistic fungus for T cells immunodeficient patients. The role of B cells and antibody play in natural resistance toEncephalitozoon cuniculiremains unresolved. Previously, we demonstrated that B-1 deficient mice (XID), an important component of innate immunity, were more susceptible to encephalitozoonosis, despite the increase in the number of CD4+and CD8+T lymphocytes. In order to better understand the role of B-1 and B-2 cells and the relationship with the other cells of the immune response in encephalitozoonosis, we infected withE. cuniculiin cyclophosphamide immunosuppressed mice. Here we demonstrate that infected XID mice showed reduction of T cells and macrophages and increase of proinflammatory cytokines associated with disseminated and severe encephalitozoonosis with presence of abdominal effusion and lesions in multiple organs. This pattern of infection observed in mice with genetic deficiency in T cells, so we suggest that the absence of B-1 cells affects the cytotoxic capacity of these lymphocytes. When we transfer B-2 cells to XID mice, the lesion areas caused by the fungus, the populations of T lymphocytes in the peritoneum and the proinflammatory cytokines decrease, indicating a better resolution of the infection. We speculate that B-1 and B-2 cells participate in the immune response againstE. cuniculi, interacting with the other components effective in immunity. The results shown here indicate that B-1 cells as a constituent of the innate response to microsporidia.

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Interleukin-10 Inhibits Bone Resorption: A Potential Therapeutic Strategy in Periodontitis and Other Bone Loss Diseases

BioMed Research International ◽

10.1155/2014/284836 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 18

Author(s):

Qian Zhang ◽

Bin Chen ◽

Fuhua Yan ◽

Jianbin Guo ◽

Xiaofeng Zhu ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

Interleukin 10 ◽

Current Therapies ◽

Anti Inflammatory ◽

Anti Inflammatory Cytokine ◽

Reduce Bone Loss

Periodontitis and other bone loss diseases, decreasing bone volume and strength, have a significant impact on millions of people with the risk of tooth loss and bone fracture. The integrity and strength of bone are maintained through the balance between bone resorption and bone formation by osteoclasts and osteoblasts, respectively, so the loss of bone results from the disruption of such balance due to increased resorption or/and decreased formation of bone. The goal of therapies for diseases of bone loss is to reduce bone loss, improve bone formation, and then keep healthy bone density. Current therapies have mostly relied on long-term medication, exercise, anti-inflammatory therapies, and changing of the life style. However there are some limitations for some patients in the effective treatments for bone loss diseases because of the complexity of bone loss. Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine, and recent studies have indicated that IL-10 can contribute to the maintenance of bone mass through inhibition of osteoclastic bone resorption and regulation of osteoblastic bone formation. This paper will provide a brief overview of the role of IL-10 in bone loss diseases and discuss the possibility of IL-10 adoption in therapy of bone loss diseases therapy.

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ASSOCIATION BETWEEN PERIODONTAL DISEASE AND OSTEOPOROSIS

Romanian Journal of Rheumatology ◽

10.37897/rjr.2017.3.1 ◽

2017 ◽

Vol 26 (3) ◽

pp. 107-114

Author(s):

Dan Piperea-Sianu ◽

◽

Adela M. Ceau ◽

Mara Carsote ◽

Alexandru G. Croitoru ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

Periodontal Disease ◽

Alveolar Bone ◽

Serum Levels ◽

Bone Lysis ◽

Local Impact ◽

Systemic Bone Loss

Osteoporosis and periodontal disease (PD) are two chronic diseases, characterized by bone loss, with systemic or local impact (alveolar bone). Both pathologies have a progressive evolution, leading to systemic bone loss in the case of osteoporosis and bone lysis localized in the alveolar bone in the case of periodontal disease. The present paper presents recent data from the literature on the association between periodontal disease and osteoporosis, on the role of cytokines in the bone resorption-apposition imbalance, and on how periodontal disease causes changes in serum levels of cytokines, leading to disorders in the systemic bone formation. We also found it useful, especially for rheumatologists, to outline the extent to which periodontal disease can create a systemic context favorable to the development of osteoporosis.

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T and B Cells in Periodontal Disease: New Functions in A Complex Scenario

International Journal of Molecular Sciences ◽

10.3390/ijms20163949 ◽

2019 ◽

Vol 20 (16) ◽

pp. 3949 ◽

Cited By ~ 10

Author(s):

C.M. Figueredo ◽

R. Lira-Junior ◽

R.M. Love

Keyword(s):

T Cells ◽

B Cells ◽

Bone Loss ◽

Periodontal Disease ◽

B Cell ◽

Dependent Manner ◽

T And B Cells ◽

Activated T Cells ◽

Mait Cells

Periodontal disease is characterised by a dense inflammatory infiltrate in the connective tissue. When the resolution is not achieved, the activation of T and B cells is crucial in controlling chronic inflammation through constitutive cytokine secretion and modulation of osteoclastogenesis. The present narrative review aims to overview the recent findings of the importance of T and B cell subsets, as well as their cytokine expression, in the pathogenesis of the periodontal disease. T regulatory (Treg), CD8+ T, and tissue-resident γδ T cells are important to the maintenance of gingival homeostasis. In inflamed gingiva, however, the secretion of IL-17 and secreted osteoclastogenic factor of activated T cells (SOFAT) by activated T cells is crucial to induce osteoclastogenesis via RANKL activation. Moreover, the capacity of mucosal-associated invariant T cells (MAIT cells) to produce cytokines, such as IFN-γ, TNF-α, and IL-17, might indicate a critical role of such cells in the disease pathogenesis. Regarding B cells, low levels of memory B cells in clinically healthy periodontium seem to be important to avoid bone loss due to the subclinical inflammation that occurs. On the other hand, they can exacerbate alveolar bone loss in a receptor activator of nuclear factor kappa-B ligand (RANKL)-dependent manner and affect the severity of periodontitis. In conclusion, several new functions have been discovered and added to the complex knowledge about T and B cells, such as possible new functions for Tregs, the role of SOFAT, and MAIT cells, as well as B cells activating RANKL. The activation of distinct T and B cell subtypes is decisive in defining whether the inflammatory lesion will stabilise as chronic gingivitis or will progress to a tissue destructive periodontitis.

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Lumican Inhibits Osteoclastogenesis and Bone Resorption by Suppressing Akt Activity

International Journal of Molecular Sciences ◽

10.3390/ijms22094717 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4717

Author(s):

Jin-Young Lee ◽

Da-Ae Kim ◽

Eun-Young Kim ◽

Eun-Ju Chang ◽

So-Jeong Park ◽

...

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Map Kinases ◽

Osteoclast Differentiation ◽

Dependent Manner ◽

Dual Action ◽

Dose Dependent ◽

Resorptive Activity

Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on osteoclast biology. Lumican inhibited both osteoclast differentiation and in vitro bone resorption in a dose-dependent manner. Consistent with this, lumican markedly decreased the expression of osteoclastogenesis markers. Moreover, the migration and fusion of preosteoclasts and the resorptive activity per osteoclast were significantly reduced in the presence of lumican, indicating that this protein affects most stages of osteoclastogenesis. Among RANKL-dependent pathways, lumican inhibited Akt but not MAP kinases such as JNK, p38, and ERK. Importantly, co-treatment with an Akt activator almost completely reversed the effect of lumican on osteoclast differentiation. Taken together, our findings revealed that lumican inhibits osteoclastogenesis by suppressing Akt activity. Thus, lumican plays an osteoprotective role by simultaneously increasing bone formation and decreasing bone resorption, suggesting that it represents a dual-action therapeutic target for osteoporosis.

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Polyclonal activation of immature B cells by preactivated T cells: the role of IL-4 and CD40 ligand

International Immunology ◽

10.1093/intimm/5.11.1445 ◽

1993 ◽

Vol 5 (11) ◽

pp. 1445-1450 ◽

Cited By ~ 24

Author(s):

Robert D. Brines ◽

Gerry G. B. Klaus

Keyword(s):

T Cells ◽

B Cells ◽

Cd40 Ligand ◽

Polyclonal Activation ◽

Immature B Cells

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Induction of autoreactive B cells allows priming of autoreactive T cells.

Journal of Experimental Medicine ◽

10.1084/jem.173.6.1433 ◽

1991 ◽

Vol 173 (6) ◽

pp. 1433-1439 ◽

Cited By ~ 175

Author(s):

R H Lin ◽

M J Mamula ◽

J A Hardin ◽

C A Janeway

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Cytochrome C ◽

Autoantibody Production ◽

Autoreactive T Cells ◽

Human Cytochrome ◽

Self Tolerance ◽

Human Cytochrome C

A novel mechanism for breaking T cell self tolerance is described. B cells induced to make autoantibody by immunization of mice with the non-self protein human cytochrome c can present the self protein mouse cytochrome c to autoreactive T cells in immunogenic form. This mechanism of breaking T cell self tolerance could account for the role of foreign antigens in breaking not only B cell but also T cell self tolerance, leading to sustained autoantibody production in the absence of the foreign antigen.

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