Denosumab Regulates Gut Microbiota Composition and Cytokines in Dinitrobenzene Sulfonic Acid (DNBS)-Experimental Colitis

Khafipour, Azin; Eissa, Nour; Munyaka, Peris M.; Rabbi, Mohammad Fazle; Kapoor, Kunal; Kermarrec, Laëtitia; Khafipour, Ehsan; Bernstein, Çharles N.; Ghia, Jean–Eric

doi:10.3389/fmicb.2020.01405

Cited by 9 publications

(9 citation statements)

References 87 publications

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“…However, very little is known regarding any connection between the use of Denosumab on the human gut microbiome and how this interaction may affect overall bone health and healing. Nevertheless, there is indirect evidence based on a recent animal study by Khafipour et al in mice with colitis, which demonstrated differing microbial diversity in mice treated with Denosumab [167]. Although the results have no direct bearing on bone homeostasis, the effects of Denosumab on bone health may either be enhanced or suppressed based on alterations in the gut microbiota.…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

The Human Gut Microbiota: A Key Mediator of Osteoporosis and Osteogenesis

Seely

Kotelko

Douglas

et al. 2021

IJMS

103

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An expanding body of research asserts that the gut microbiota has a role in bone metabolism and the pathogenesis of osteoporosis. This review considers the human gut microbiota composition and its role in osteoclastogenesis and the bone healing process, specifically in the case of osteoporosis. Although the natural physiologic processes of bone healing and the pathogenesis of osteoporosis and bone disease are now relatively well known, recent literature suggests that a healthy microbiome is tied to bone homeostasis. Nevertheless, the mechanism underlying this connection is still somewhat enigmatic. Based on the literature, a relationship between the microbiome, osteoblasts, osteoclasts, and receptor activator of nuclear factor-kappa-Β ligand (RANKL) is contemplated and explored in this review. Studies have proposed various mechanisms of gut microbiome interaction with osteoclastogenesis and bone health, including micro-RNA, insulin-like growth factor 1, and immune system mediation. However, alterations to the gut microbiome secondary to pharmaceutical and surgical interventions cannot be discounted and are discussed in the context of clinical therapeutic consideration. The literature on probiotics and their mechanisms of action is examined in the context of bone healing. The known and hypothesized interactions of common osteoporosis drugs and the human gut microbiome are examined. Since dysbiosis in the gut microbiota can function as a biomarker of bone metabolic activity, it may also be a pharmacological and nutraceutical (i.e., pre- and probiotics) therapeutic target to promote bone homeostasis.

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Section: Monoclonal Antibodiesmentioning

confidence: 99%

The Human Gut Microbiota: A Key Mediator of Osteoporosis and Osteogenesis

Seely

Kotelko

Douglas

et al. 2021

IJMS

103

View full text Add to dashboard Cite

show abstract

“…Catecholamine norepinephrine increases cardiac MMP-2 activity and collagen deposition [ 104 ], thus indicating that adrenergic receptors’ activation enhances MMP activity. In fact, the antagonist of β-adrenergic receptors, nebivolol, attenuates hypertension-induced vascular remodeling and increases vascular MMP-2 activity [ 105 ]. Similar effects are also reported in the hearts of hypertensive animals [ 106 ].…”

Section: Imbalanced Vascular Mmp Activity Activates Critical Mechanisms Leading To Vascular Remodeling In Hypertensionmentioning

confidence: 99%

“…MMP-2 and MMP-9 are also responsible for activating cytokines, such as transforming growth factor-β (TGF-β), which are involved in collagen accumulation and profibrotic alterations in remodeling that are associated with hypertension [ 105 ]. Tumor necrosis factor-α (TNF-α) is another cytokine implicated in the vascular remodeling of hypertension, as it is essential for Ang-II-induced MMP-2 expression [ 107 ].…”

Section: Imbalanced Vascular Mmp Activity Activates Critical Mechanisms Leading To Vascular Remodeling In Hypertensionmentioning

confidence: 99%

Matrix Metalloproteinases and Arterial Hypertension: Role of Oxidative Stress and Nitric Oxide in Vascular Functional and Structural Alterations

et al. 2021

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Various pathophysiological mechanisms have been implicated in hypertension, but those resulting in vascular dysfunction and remodeling are critical and may help to identify critical pharmacological targets. This mini-review article focuses on central mechanisms contributing to the vascular dysfunction and remodeling of hypertension, increased oxidative stress and impaired nitric oxide (NO) bioavailability, which enhance vascular matrix metalloproteinase (MMP) activity. The relationship between NO, MMP and oxidative stress culminating in the vascular alterations of hypertension is examined. While the alterations of hypertension are not fully attributable to these pathophysiological mechanisms, there is strong evidence that such mechanisms play critical roles in increasing vascular MMP expression and activity, thus resulting in abnormal degradation of extracellular matrix components, receptors, peptides, and intracellular proteins involved in the regulation of vascular function and structure. Imbalanced vascular MMP activity promotes vasoconstriction and impairs vasodilation, stimulating vascular smooth muscle cells (VSMC) to switch from contractile to synthetic phenotypes, thus facilitating cell growth or migration, which is associated with the deposition of extracellular matrix components. Finally, the protective effects of MMP inhibitors, antioxidants and drugs that enhance vascular NO activity are briefly discussed. Newly emerging therapies that address these essential mechanisms may offer significant advantages to prevent vascular remodeling in hypertensive patients.

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“…Inhibition of RANKL may have an additional impact on skeletal muscle with early clinical data showing a reduction in the risk of falls and improved markers of sarcopenia in elderly patients [ 160 ]. Additionally, Denosumab was recently found to reduce colonic expression of pro-inflammatory cytokines and modulate disruption of the microbiome in a murine model of colitis mimicking CD [ 161 ], suggesting a potential role for RANKL in disease pathogenesis. Despite this, Denosumab remains relatively unexplored in IBD and further investigation of its impact on bone, muscle and disease outcomes in pre-clinical and human IBD studies is required.…”

Section: Future Directionsmentioning

confidence: 99%

Pathogenesis of Musculoskeletal Deficits in Children and Adults with Inflammatory Bowel Disease

et al. 2021

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Musculoskeletal deficits are among the most commonly reported extra-intestinal manifestations and complications of inflammatory bowel disease (IBD), especially in those with Crohn’s disease. The adverse effects of IBD on bone and muscle are multifactorial, including the direct effects of underlying inflammatory disease processes, nutritional deficits, and therapeutic effects. These factors also indirectly impact bone and muscle by interfering with regulatory pathways. Resultantly, individuals with IBD are at increased risk of osteoporosis and sarcopenia and associated musculoskeletal morbidity. In paediatric IBD, these factors may contribute to suboptimal bone and muscle accrual. This review evaluates the main pathogenic factors associated with musculoskeletal deficits in children and adults with IBD and summarises the current literature and understanding of the musculoskeletal phenotype in these patients.

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Denosumab Regulates Gut Microbiota Composition and Cytokines in Dinitrobenzene Sulfonic Acid (DNBS)-Experimental Colitis

Cited by 9 publications

References 87 publications

The Human Gut Microbiota: A Key Mediator of Osteoporosis and Osteogenesis

The Human Gut Microbiota: A Key Mediator of Osteoporosis and Osteogenesis

Matrix Metalloproteinases and Arterial Hypertension: Role of Oxidative Stress and Nitric Oxide in Vascular Functional and Structural Alterations

Pathogenesis of Musculoskeletal Deficits in Children and Adults with Inflammatory Bowel Disease

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