Endogenous Glucocorticoids and Bone

Abstract

While the adverse effects of glucocorticoids on bone are well described, positive effects of glucocorticoids on the differentiation of osteoblasts are also observed. These paradoxical effects of glucocorticoids are dose dependent. At both physiologicaland supraphysiological levels of glucocorticoids, osteoblasts and osteocytes are the major glucocorticoid target cells. However, the response of the osteoblasts to each of these is quite distinct. At physiology levels, glucocorticoids direct mesenchymal progenitor cells to differentiate towards osteoblasts and thus increase bone formation in a positive way. In contrast with ageing, the excess production of glucocorticoids, at both systemic and intracellular levels, appear to impact on osteoblast and osteocytes in a negative way in a similar fashion to that seen with therapeutic glucocorticoids. This review will focus on therole of glucocorticoids in normal bone physiology, with particular emphasis on the mechanism by which endogenous glucocorticoids impact on bone and its constituent cells.

Keywords: Wnt signaling; bone; glucocorticoids; mechanisms of action; osteoblasts; skeletal development.

Figure 1

The mechanisms of action of glucocorticoids. Glucocorticoids, cortisone (in man) or dehydro-corticosterone (in rodents) are activated by 11β-HSD1 to cortisol or corticosterone which then binds to their receptor (GR), after which the activated ligand-receptor-complex travels to the nucleus. The activated GR can either bind to its specific response element (GRE) or bind to other transcription factors such as AP-1 (fos and jun) pathway.

Figure 2

Model of osteoblast differentiation and the putative stage of transgene expression. Diagram showing the expression of transgenes under the control of various promoters active along the mesenchymal/osteoblastic lineage. Dermo1 promoter (31,32) is activated in early multi-potential cells. Runx2 (33,88,89) and Osterix (89,90) are the two well characterized promoters activated in early committed osteoblastic progenitors; Col3.6 promoter (91,92) is expressed after osterix expression in pre-osteoblasts at the stages in which cells express type I collagen (Collagen 1) and subsequently alkaline phosphatase (ALP); Col2.3 promoter (91,92) is expressed in mature osteoblasts which express Wnt7b and then Dkk2 which switch on mineralization (47); Osteocalcin promoter (OG2) is active at the later stage of mature osteoblasts when mineralization has been initiated (11,57,58,93). Both Col2.3 and OG2 promoters are expressed in osteocytes.

Figure 3

Glucocorticoids control of lineage commitment of mesenchymal progenitors through mature osteoblast via Wnt signaling. Glucocorticoids stimulate osteoblasts to increase secretion of Wnts and to decrease secretion of the Wnt inhibitor, sFRP1; both actions would advance canonical Wnt signaling in mesenchymal progenitor cells which in turn, causes β-catenin to enter the nucleus which increases Runx2 expression while inhibiting PPARg expression. These actions promote osteoblastogenesis but inhibit adipogenesis.

Figure 4

Model of glucocorticoid dependent canonical Wnt signaling in cranial development. Glucocorticoids stimulate mature osteoblasts to produce canonical Wnt proteins, which activate the β-catenin signaling cascade in: (A) cranial mesenchymal progenitor cells, through up-regulation of Runx2 and down-regulation of Sox9 expression, to differentiate towards osteoblasts and away from chondrocytes; (B) osteoblasts, through up-regulation of DKK2 terminating osteoblast differentiation and leading to mineralization; up-regulation of MMP14 to initiate the remodelling of the collagenous matrix surrounding the osteoblast; (C) cranial chondrocytes, through up-regulation of MMP14 to initiate the cranial cartilage degradation.