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Dissociation of osteogenic and immunological effects by the selective glucocorticoid receptor agonist, compound A, in human bone marrow stromal cells

(2011) ENDOCRINOLOGY. 152(1). p.103-112
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Abstract
Glucocorticoids (GCs) regulate various physiological processes, including bone remodeling. Whereas physiological amounts of GCs are required for proper human osteoblast differentiation, prolonged exposure to GCs leads to substantial bone loss in vivo predominantly by inhibiting osteoblast functions. Compound A (CpdA) is a novel GC receptor modulator with the potential of an improved benefit/risk profile. Here we tested the osteoimmunological effects of CpdA on primary human osteoblasts and their paracrine interactions with osteoclasts. To assess the anti-inflammatory potential of CpdA in human bone marrow stromal cell (BMSC)-derived osteoblasts, cells were stimulated with lipopolysaccharide and cytokine expression was determined. Similar to dexamethasone (DEX), CpdA profoundly suppressed lipopolysaccharide-induced TNF-alpha (-63%), IL-1 beta (-38%), and IL-6 (-36%) (P < 0.05) mRNA levels. Of note, CpdA failed to induce osteogenic differentiation of BMSCs, whereas DEX and budesonide enhanced matrix mineralization an d increased runt-related transcription factor 2 and alkaline phosphatase mRNA levels up to 5-fold in a dose-dependent manner. Interestingly, each substancepromotedcell proliferation by 7-10% and suppressed apoptosis by 25-30% at low concentrations and early differentiation stages, whereas high concentrations (1 mu M) suppressed proliferation and stimulated apoptosis in mature osteoblasts. Finally, CpdA did not increase the receptor activator of nuclear factor-kappa B ligand to osteoprotegerin mRNA ratio as compared with DEX and did not stimulate the formation of osteoclasts in coculture with BMSCs. In summary, CpdA displays dissociated osteogenic and immunological effects in human BMSCs that are distinct from those of conventional GCs. Whether the specific osteoimmunological profile of CpdA translates into a relevant in vivo effect needs to be further explored. (Endocrinology 152: 103-112, 2011)
Keywords
INDUCED OSTEOPOROSIS, INHIBITION, OSTEOBLAST DIFFERENTIATION, RANKL, OSTEOCLASTOGENESIS, TRANSACTIVATION, OSTEOPROTEGERIN, PREVENTION, APOPTOSIS, MODULATOR

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Citation

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Chicago
Rauner, Martina, Claudia Goettsch, Nicola Stein, Sylvia Thiele, Martin Bornhaeuser, Karolien De Bosscher, Guy Haegeman, Jan Tuckermann, and Lorenz C Hofbauer. 2011. “Dissociation of Osteogenic and Immunological Effects by the Selective Glucocorticoid Receptor Agonist, Compound A, in Human Bone Marrow Stromal Cells.” Endocrinology 152 (1): 103–112.
APA
Rauner, M., Goettsch, C., Stein, N., Thiele, S., Bornhaeuser, M., De Bosscher, K., Haegeman, G., et al. (2011). Dissociation of osteogenic and immunological effects by the selective glucocorticoid receptor agonist, compound A, in human bone marrow stromal cells. ENDOCRINOLOGY, 152(1), 103–112.
Vancouver
1.
Rauner M, Goettsch C, Stein N, Thiele S, Bornhaeuser M, De Bosscher K, et al. Dissociation of osteogenic and immunological effects by the selective glucocorticoid receptor agonist, compound A, in human bone marrow stromal cells. ENDOCRINOLOGY. 2011;152(1):103–12.
MLA
Rauner, Martina, Claudia Goettsch, Nicola Stein, et al. “Dissociation of Osteogenic and Immunological Effects by the Selective Glucocorticoid Receptor Agonist, Compound A, in Human Bone Marrow Stromal Cells.” ENDOCRINOLOGY 152.1 (2011): 103–112. Print.
@article{1150757,
  abstract     = {Glucocorticoids (GCs) regulate various physiological processes, including bone remodeling. Whereas physiological amounts of GCs are required for proper human osteoblast differentiation, prolonged exposure to GCs leads to substantial bone loss in vivo predominantly by inhibiting osteoblast functions. Compound A (CpdA) is a novel GC receptor modulator with the potential of an improved benefit/risk profile. Here we tested the osteoimmunological effects of CpdA on primary human osteoblasts and their paracrine interactions with osteoclasts. To assess the anti-inflammatory potential of CpdA in human bone marrow stromal cell (BMSC)-derived osteoblasts, cells were stimulated with lipopolysaccharide and cytokine expression was determined. Similar to dexamethasone (DEX), CpdA profoundly suppressed lipopolysaccharide-induced TNF-alpha (-63\%), IL-1 beta (-38\%), and IL-6 (-36\%) (P {\textlangle} 0.05) mRNA levels. Of note, CpdA failed to induce osteogenic differentiation of BMSCs, whereas DEX and budesonide enhanced matrix mineralization an d increased runt-related transcription factor 2 and alkaline phosphatase mRNA levels up to 5-fold in a dose-dependent manner. Interestingly, each substancepromotedcell proliferation by 7-10\% and suppressed apoptosis by 25-30\% at low concentrations and early differentiation stages, whereas high concentrations (1 mu M) suppressed proliferation and stimulated apoptosis in mature osteoblasts. Finally, CpdA did not increase the receptor activator of nuclear factor-kappa B ligand to osteoprotegerin mRNA ratio as compared with DEX and did not stimulate the formation of osteoclasts in coculture with BMSCs. In summary, CpdA displays dissociated osteogenic and immunological effects in human BMSCs that are distinct from those of conventional GCs. Whether the specific osteoimmunological profile of CpdA translates into a relevant in vivo effect needs to be further explored. (Endocrinology 152: 103-112, 2011)},
  author       = {Rauner, Martina and Goettsch, Claudia and Stein, Nicola and Thiele, Sylvia and Bornhaeuser, Martin and De Bosscher, Karolien and Haegeman, Guy and Tuckermann, Jan and Hofbauer, Lorenz C},
  issn         = {0013-7227},
  journal      = {ENDOCRINOLOGY},
  keyword      = {INDUCED OSTEOPOROSIS,INHIBITION,OSTEOBLAST DIFFERENTIATION,RANKL,OSTEOCLASTOGENESIS,TRANSACTIVATION,OSTEOPROTEGERIN,PREVENTION,APOPTOSIS,MODULATOR},
  language     = {eng},
  number       = {1},
  pages        = {103--112},
  title        = {Dissociation of osteogenic and immunological effects by the selective glucocorticoid receptor agonist, compound A, in human bone marrow stromal cells},
  url          = {http://dx.doi.org/10.1210/en.2010-0456},
  volume       = {152},
  year         = {2011},
}

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