title: Dissociation of osteogenic and immunological effects by the selective glucocorticoid receptor agonist, compound A, in human bone marrow stromal cells.
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 antiinflammatory 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-α (-63%), IL-1β (-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 substance promoted cell proliferation by 7-10% and suppressed apoptosis by 25-30% at low concentrations and early differentiation stages, whereas high concentrations (1 μm) suppressed proliferation and stimulated apoptosis in mature osteoblasts. Finally, CpdA did not increase the receptor activator of nuclear factor-κB 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.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolic Bone Diseases, Department of Medicine III, Dresden Technical University Medical Center, Fetscherstrasse 74, 01307 Dresden, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
authors.forename: Claudia
authors.initials: C
authors.lastname: Goettsch
authors.forename: Nicola
authors.initials: N
authors.lastname: Stein
authors.forename: Sylvia
authors.initials: S
authors.lastname: Thiele
authors.forename: Martin
authors.initials: M
authors.lastname: Bornhaeuser
authors.forename: Karolien
authors.initials: K
authors.lastname: De Bosscher
authors.forename: Guy
authors.initials: G
authors.lastname: Haegeman
authors.forename: Jan
authors.initials: J
authors.lastname: Tuckermann
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
mesh_terms: D000085:Acetates / Q000819:agonists*; D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D005021:Ethylamines / Q000819:agonists*; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014439:Tyramine / Q000031:analogs & derivatives; D055815:Young Adult
chemical_list: C104564:2-(4-acetoxyphenyl)-2-chloro-N-methylethylamine; D000085:Acetates; D005021:Ethylamines; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D014439:Tyramine