The Localization of the Functional Glucocorticoid Receptor α in Human Bone

Abstract

Glucocorticoids have well-documented effects on the skeleton, although their mechanism of action is still poorly understood. The actions of glucocorticoids on bone cells are mediated, in part, directly via specific receptors. The presence of these receptors has been demonstrated in both rodent and human osteoblastic cells in vitro, but their presence in human bone in vivo has not been reported. In this study, we have used specific affinity purified polyclonal antibodies to the functional glucocorticoid receptor alpha (GRalpha) to investigate its expression in both developing and adult human bone using sections of neonatal rib, calvarial, and vertebral bones, tibial growth plates from adolescents, and iliac crest biopsies from adults who were to undergo liver transplantation. In the tibial growth plates, GRalpha was predominantly expressed in the hypertrophic chondrocytes within the cartilage. In the primary spongiosa, the receptor was highly expressed by osteoblasts at sites of bone modeling. Within the bone marrow, receptors were also detected in mononuclear cells and in endothelial cells of blood vessels. In the neonatal rib and vertebrae, GRalpha was widely distributed at sites of endochondral bone formation in resting, proliferating, mature, and hypertrophic chondrocytes. They were also highly expressed in osteoblasts at sites of bone modeling. At sites of intramembranous ossification in neonatal calvarial bone and rib periosteum, GRa was widely expressed in cells within the fibrous tissue and in osteoblasts at both the bone-forming surface and at modeling sites. In the iliac crests from adults, GRalpha was predominantly expressed in osteocytes. The receptors were not detected in osteoclasts. Our results show for the first time the presence of the functional GRalpha in human bone in situ and suggest that the actions of glucocorticoids on bone may be mediated, in part, directly via the GR at different stages of life. The absence of receptor expression in osteoclasts also suggests that the effects of glucocorticoids on bone resorption may be mediated indirectly.

Glucocorticoids, Thyroid Hormone and Growth Hormone Interactions: Implications for the Growth Plate

“…These findings have been supported by studies that demonstrate GC receptor expression in growth plate chondrocytes and in osteoblasts and osteocytes [32, 33]. Some of the actions of GC, however, may be mediated via IGF-I, and GC may also modify skeletal responses to GH and IGF-I.…”

Systemic and Local Regulation of the Growth Plate

“…A few studies have now localized the GC receptor (GR) in rat bone cells, including chondrocytes (122), and in human growth plates, especially in hypertrophic chondrocytes, suggesting direct effects of GC on the growth plate (123).…”

Effects of Chemotherapy on Bone Metabolism and Skeletal Growth

“…Evidence for a direct effect of GCs on the growth plate came from a study in which local dexamethasone infusion markedly decreased tibial growth compared with the contralateral limb [27]. The glucocorticoid receptor (GR) has since been identified in proliferating and hypertrophic chondrocytes and in osteoblasts and osteocytes in the rat [28]and mainly in hypertrophic chondrocytes and osteoblasts, at sites of bone remodelling, in human growth plates [29]. …”