Glucocorticoid Signaling and Bone Biology

Abstract

Glucocorticoid Signaling and Bone Biology issue in rodent models of GC-induced osteoporosis is that the loss of cancellous bone is not consistently observed in rodents. GC treatments in large animals, including rabbits and sheep, show a similar phenotype to that in humans [3]. GC receptor (GR, official symbol Nr3c1) forms a complex containing chaperone molecules including HSP90 in the cytoplasm. Ligand binding to GR results in the dissociation of the complex and GR translocates into the nucleus. The GR homodimer directly binds GC responsive elements (GREs) in DNA and upregulates or suppresses the transcription of associated genes. Monomeric GR is also involved in the regulation of gene transcription. It binds to transcription factors by proteinprotein interactions and promotes or inhibits gene transcription [4].

RANKL/RANK/OPG Axis Is Deregulated in the Cerebrospinal Fluid of Multiple Sclerosis Patients at Clinical Onset

“…However, we cannot rule out that our findings in the RR-MS patients were influenced by the treatment. RR-MS patients receive glucocorticoids during disease relapses, and it is known that glucocorticoids may increase the RANKL level [33][34][35]. It is important to stress that patients were not on glucocorticoid treatment for at least 2 years prior to sampling.…”

“…Systemic inflammatory parameters (leukocyte count, ESR, and CRP) were within the physiologic range in all groups (< 5 mg/L for CRP and < 15 mm/h for ESR; not shown). Compared to healthy (control) subjects, there were no differences in age (median [IQR]: 43 [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] years for controls, 36 for MS patients at clinical onset, and 38 [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] for RR-MS patients) and sex (male/female ratio: 15/20 for controls, 16/17 for MS patients at clinical onset, and 8/22 for RR-MS patients).…”

Advances in treatment of glucocorticoid-induced osteoporosis

“…In terms of the direct impact on bone, endogenous glucocorticoids at physiologic concentrations may have a role in promoting osteogenesis[3], while excess glucocorticoids increase osteoclastogenesis and suppress osteblastogenesis in cell culture, murine, and human models[4, 5]. Local metabolism of glucocorticoids in bone cells is controlled by a pair of complementary enzymes, 11β-hydroxysteroid dehydrogenase types 1 and 2 (Hsd11b1 & Hsd11b2), which respectively activate or deactivate glucocorticoid action by metabolizing the interconversion of biologically active or inert forms[6, 7].…”

“…Local metabolism of glucocorticoids in bone cells is controlled by a pair of complementary enzymes, 11β-hydroxysteroid dehydrogenase types 1 and 2 (Hsd11b1 & Hsd11b2), which respectively activate or deactivate glucocorticoid action by metabolizing the interconversion of biologically active or inert forms[6, 7]. Additional pathways of glucocorticoid action are thought to be multiple, including inducing proapoptotic molecules in osteoblasts and osteocytes, and through antagonizing the osteoblastogenic Wnt pathway [4, 8, 9]. There continues to be active work into uncovering pathways of glucocorticoid mechanism at the cellular level[10], including recent claims of enhancing osteoblast activity through heat shock protein 90[11].…”

Osteoporosis: what the clinician needs to know?

“…Osteoporosis can be distinguished as primary or secondary (4). Primary osteoporosis is caused by changes in normal bone turnover; these can be secondary to reduction of bone matrix production due to low osteoblastic activity, as it happens in postmenopausal women (following the loss of estrogen protection on bone matrix) (4), or in adult population for the aging of cortical and cancellous bone (5); otherwise, primary osteoporosis can be secondary to increased osteoblastic activity, as may result during corticosteroid treatments (2,6) Secondary osteoporosis can be associated to several conditions, such as congenital (i.e., osteogenesis imperfecta, Ehlers-Danlos syndrome, Marfan syndrome), malnutrition (i.e., vitamin D deficiency, low calcium intake), metabolic, endocrine or iatrogenic diseases (3,5).…”