Glucocorticoid Excess in Bone and Muscle

Sato, Amy Y.; Bellido, Teresita

doi:10.1007/s12018-018-9242-3

Cited by 38 publications

(31 citation statements)

References 173 publications

(212 reference statements)

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“…Glucocorticoids (GCs) are extensively used for the treatment of immune and inflammatory disorders due to their powerful immunosuppressive and anti-inflammatory actions ( 91 , 92 ). However, long-term exogenous GC therapy might cause rapid and pronounced bone loss and subsequently osteoporosis ( 93 , 94 ).…”

Section: The T Cells In the Regulation Of Various Osteoporosismentioning

confidence: 99%

Osteoimmunology: The Regulatory Roles of T Lymphocytes in Osteoporosis

et al. 2020

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Immune imbalance caused bone loss. Osteoimmunology is emerging as a new interdisciplinary field to explore the shared molecules and interactions between the skeletal and immune systems. In particular, T lymphocytes (T cells) play pivotal roles in the regulation of bone health. However, the roles and mechanisms of T cells in the treatment of osteoporosis are not fully understood. The present review aims to summarize the essential regulatory roles of T cells in the pathophysiology of various cases of osteoporosis and the development of T cell therapy for osteoporosis from osteoimmunology perspective. As T cell-mediated immunomodulation inhibition reduced bone loss, there is an increasing interest in T cell therapy in an attempt to treat osteoporosis. In summary, the T cell therapy may be further pursued as an immunomodulatory strategy for the treatment of osteoporosis, which can provide a novel perspective for drug development in the future.

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Section: The T Cells In the Regulation Of Various Osteoporosismentioning

confidence: 99%

Osteoimmunology: The Regulatory Roles of T Lymphocytes in Osteoporosis

et al. 2020

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“…(11) However, abnormal increases in endogenous cortisol levels associated with aging (12,13) and possibly anorexia, (14) as well as pharmacologic doses of exogenous GCs can decrease osteoblast differentiation and viability. (11,15) GC treatment has been shown to induce apoptosis of osteoblasts as well as osteocytes in both mouse (5,16,17) and human (18)(19)(20)(21)(22) bone samples. In addition, GCs have been shown to skew mesenchymal stem cell differentiation toward adipocytes and thus impair osteoblast lineage selection and differentiation.…”

mentioning

confidence: 99%

Involvement of the Gut Microbiota and Barrier Function in Glucocorticoid-Induced Osteoporosis

Schepper

Collins

Rios‐Arce

et al. 2019

Journal of Bone and Mineral Research

123

119

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Glucocorticoids (GCs) are potent immune‐modulating drugs with significant side effects, including glucocorticoid‐induced osteoporosis (GIO). GCs directly induce osteoblast and osteocyte apoptosis but also alter intestinal microbiota composition. Although the gut microbiota is known to contribute to the regulation of bone density, its role in GIO has never been examined. To test this, male C57/Bl6J mice were treated for 8 weeks with GC (prednisolone, GC‐Tx) in the presence or absence of broad‐spectrum antibiotic treatment (ABX) to deplete the microbiota. Long‐term ABX prevented GC‐Tx‐induced trabecular bone loss, showing the requirement of gut microbiota for GIO. Treatment of GC‐Tx mice with a probiotic (Lactobacillus reuteri [LR]) prevented trabecular bone loss. Microbiota analyses indicated that GC‐Tx changed the abundance of Verrucomicobiales and Bacteriodales phyla and random forest analyses indicated significant differences in abundance of Porphyromonadaceae and Clostridiales operational taxonomic units (OTUs) between groups. Furthermore, transplantation of GC‐Tx mouse fecal material into recipient naïve, untreated WT mice caused bone loss, supporting a functional role for microbiota in GIO. We also report that GC caused intestinal barrier breaks, as evidenced by increased serum endotoxin level (2.4‐fold), that were prevented by LR and ABX treatments. Enhancement of barrier function with a mucus supplement prevented both GC‐Tx–induced barrier leakage and trabecular GIO. In bone, treatment with ABX, LR or a mucus supplement reduced GC‐Tx–induced osteoblast and osteocyte apoptosis. GC‐Tx suppression of Wnt10b in bone was restored by the LR and high‐molecular‐weight polymer (MDY) treatments as well as microbiota depletion. Finally, we identified that bone‐specific Wnt10b overexpression prevented GIO. Taken together, our data highlight the previously unappreciated involvement of the gut microbiota and intestinal barrier function in trabecular GIO pathogenesis (including Wnt10b suppression and osteoblast and osteocyte apoptosis) and identify the gut as a novel therapeutic target for preventing GIO. © 2019 American Society for Bone and Mineral Research.

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“…High dose of glucocorticoids (GCs) is a frequent component of anti-MM therapy due to its ability to induce apoptosis of MM cells and capacity to enhance the efficacy of other chemotherapy drugs [18–20]. However, GCs cause rapid bone loss by increasing bone resorption, inducing osteoblast and osteocyte apoptosis, and reducing bone formation [21–23]. In contrast, Btz, also used as a frontline agent for the treatment of MM, can induce transient decreases in bone resorption and increase osteoblast number and bone formation markers [24].…”

Section: Discussionmentioning

confidence: 99%

Aplidin (plitidepsin) is a novel anti-myeloma agent with potent anti-resorptive activity mediated by direct effects on osteoclasts

et al. 2019

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Despite recent progress in its treatment, Multiple Myeloma (MM) remains incurable and its associated bone disease persists even after complete remission. Thus, identification of new therapeutic agents that simultaneously suppress MM growth and protect bone is an unmet need. Herein, we examined the effects of Aplidin, a novel anti-cancer marine-derived compound, on MM and bone cells. In vitro, Aplidin potently inhibited MM cell growth and induced apoptosis, effects that were enhanced by dexamethasone (Dex) and bortezomib (Btz). Aplidin modestly reduced osteocyte/osteoblast viability and decreased osteoblast mineralization, effects that were enhanced by Dex and partially prevented by Btz. Further, Aplidin markedly decreased osteoclast precursor numbers and differentiation, and reduced mature osteoclast number and resorption activity. Moreover, Aplidin reduced Dex-induced osteoclast differentiation and further decreased osteoclast number when combined with Btz. Lastly, Aplidin alone, or suboptimal doses of Aplidin combined with Dex or Btz, decreased tumor growth and bone resorption in ex vivo bone organ cultures that reproduce the 3D-organization and the cellular diversity of the MM/bone marrow niche. These results demonstrate that Aplidin has potent anti-myeloma and anti-resorptive properties, and enhances proteasome inhibitors blockade of MM growth and bone destruction.

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Glucocorticoid Excess in Bone and Muscle

Cited by 38 publications

References 173 publications

Osteoimmunology: The Regulatory Roles of T Lymphocytes in Osteoporosis

Osteoimmunology: The Regulatory Roles of T Lymphocytes in Osteoporosis

Involvement of the Gut Microbiota and Barrier Function in Glucocorticoid-Induced Osteoporosis

Aplidin (plitidepsin) is a novel anti-myeloma agent with potent anti-resorptive activity mediated by direct effects on osteoclasts

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