Activation of dimeric glucocorticoid receptors in osteoclast progenitors potentiates RANKL induced mature osteoclast bone resorbing activity.
Glucocorticoid (GC) therapy is the greatest risk factor for secondary osteoporosis. Pathogenic mechanisms involve an initial increase in bone resorption followed by decreased bone formation. To gain a better understanding of the resorptive activity of GCs, we have used mouse bone marrow macrophages (BMM) to determine if GCs can directly modulate RANKL stimulated osteoclast formation and/or activity. In agreement with previous studies, experiments performed in plastic wells showed that GCs (dexamethasone, hydrocortisone, and prednisolone) inhibited osteoclast number and size during the initial phases of RANKL stimulated osteoclastogenesis; however, in prolonged cultures, decreased apoptosis was observed and escape from GC induced inhibition occurred with an enhanced number of osteoclasts formed, many with an increased area. When BMM cells were seeded on bone slices, GCs robustly enhanced RANKL stimulated formation of resorption pits and release of CTX without affecting the number or size of osteoclasts formed and with no effect on apoptosis. Stimulation of pit formation was not associated with increased life span of osteoclasts or an effect on mRNA expression of several osteoclastic or osteoclastogenic genes. The potentiation of RANKL induced CTX release by dexamethasone was significantly less in BMM cells from mice with conditional knockout of the osteoclastic glucocorticoid receptor and completely absent in cells from GRdimmice, which carry a point mutation in one dimerizing interface of the GC receptor. These data suggest that: 1. Plastic is a poor medium to use for studying direct effects of GCs on osteoclasts 2. GCs can enhance bone resorption without decreasing apoptosis, and 3. A direct enhancement of RANKL mediated resorption is stimulated by the dimeric GC-receptor.
Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
H Herschel
HH
Conaway
Centre for Bone and Arthritis Research at Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Petra
P
Henning
Department of Molecular Periodontology, Umeå University, Umeå, Sweden.
Anita
A
Lie
Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany.
Jan
J
Tuckermann
Centre for Bone and Arthritis Research at Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Department of Molecular Periodontology, Umeå University, Umeå, Sweden. Electronic address: ulf.lerner@gu.se.
Ulf H
UH
Lerner
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D015726:Giant Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005938:Glucocorticoids / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D010455:Peptides / Q000378:metabolism; D055503:Protein Multimerization; D053245:RANK Ligand / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*
D015415:Biomarkers; D024042:Collagen Type I; D005938:Glucocorticoids; D010455:Peptides; D053245:RANK Ligand; D011965:Receptors, Glucocorticoid; C052929:collagen type I trimeric cross-linked peptide; D003907:Dexamethasone
Bone resorption; Glucocorticoid; Glucocorticoid receptor; Osteoclast; Osteoporosis