Glucocorticoids and bone: local effects and systemic implications

•Endogenous glucocorticoids are required for normal bone development and bone cell function. •Excess glucocorticoids are detrimental to bone structure and strength through their negative effects on osteoblast and osteocyte function. •Osteoanabolic agents may prove superior to bisphosphonates in the treatment of glucocorticoid-induced osteoporosis. •The suppression of osteoblast function and osteocalcin synthesis plays an important role in glucocorticoid-induced diabetes and obesity. Glucocorticoids (GCs) are highly effective in the treatment of inflammatory and autoimmune conditions but their therapeutic use is limited by numerous adverse effects. Recent insights into the mechanisms of action of both endogenous and exogenous GCs on bone cells have unlocked new approaches to the development of effective strategies for the prevention and treatment of GC-induced osteoporosis. Furthermore, topical studies in rodents indicate that the osteoblast-derived peptide, osteocalcin, plays a central role in the pathogenesis of GC-induced diabetes and obesity. These exciting findings mechanistically link the detrimental effects of GCs on bone and energy metabolism. In this article we review the physiology and pathophysiology of GC action on bone cells, and discuss current and emerging concepts regarding the molecular mechanisms underlying adverse effects of GCs such as osteoporosis and diabetes. Glucocorticoids (GCs) are highly effective in the treatment of inflammatory and autoimmune conditions but their therapeutic use is limited by numerous adverse effects. Recent insights into the mechanisms of action of both endogenous and exogenous GCs on bone cells have unlocked new approaches to the development of effective strategies for the prevention and treatment of GC-induced osteoporosis. Furthermore, topical studies in rodents indicate that the osteoblast-derived peptide, osteocalcin, plays a central role in the pathogenesis of GC-induced diabetes and obesity. These exciting findings mechanistically link the detrimental effects of GCs on bone and energy metabolism. In this article we review the physiology and pathophysiology of GC action on bone cells, and discuss current and emerging concepts regarding the molecular mechanisms underlying adverse effects of GCs such as osteoporosis and diabetes. an adipokine that is secreted by adipocytes and influences several metabolic pathways to improve insulin resistance. comprises both pro- and antiapoptotic molecules. Generally, BCL-2-related molecules alter cell fate by either promoting or reducing membrane permeability in mitochondria. a class of pharmacological agents that reduce bone turnover and bone loss by inducing osteoclast apoptosis. Various oral and intravenous preparations are available for the treatment of osteoporosis (see Table 2 in main text). the process by which osteoblasts form new bone by laying down the organic bone matrix ('osteoid'), which subsequently becomes mineralized. a constant and lifelong process by which existing bone is removed (bone resorption) and replaced with new bone (bone formation). In adults, about 10% of the skeletal mass is turned over every year. the process of breaking down and removing bone tissue by osteoclasts. the downstream effector of the canonical Wnt signalling pathway. After translocation into the nucleus, β-catenin alters gene transcription profiles in conjunction with the TCF/LEF family transcription factors. most bones consist of two distinct compartments, cortical (or compact) and trabecular (or cancellous) bone. Trabecular bone is located at the proximal and distal ends of long bones and in the interior parts of the vertebrae, whereas cortical bone forms the outer shell. Cortical bone is denser and stiffer than the more elastic and metabolically active trabecular bone. two closely related enzymes that determine the local availability of the active GC cortisol by conversion of metabolically inactive cortisone into active cortisol (11β-HSD type 1) or vice versa (11β-HSD type 2). 11β-HSD2 is frequently used in transgenic mouse models to disrupt GC signalling selectively in defined cell populations (e.g., in osteoblasts). bone-forming cells derived from mesenchymal progenitor cells. A subset of osteoblast develops into osteocytes. a protein synthesised exclusively by osteoblasts and osteocytes. It is highly abundant in skeletal tissues and can be measured in the circulation. Serum osteocalcin levels correlate with both bone formation and some metabolic parameters such as fasting glucose. multinuclear bone-resorbing cells derived from the monocyte–macrophage cell lineage. the terminal differentiation products of osteoblasts; they reside in the lacunar–canalicular network of mineralized bone were they fulfil multiple functions, including mechanosensing and control of osteoblast and osteoclast cell populations. a naturally occurring decoy receptor for RANKL, which inhibits the recruitment, differentiation, and activation of osteoclasts. OPG is secreted by osteoblasts, along with RANKL. a peptide hormone of 84 amino acids secreted by the parathyroid glands. It has an important role in regulating systemic calcium and phosphate homeostasis, as well as in bone turnover. a surface receptor expressed by osteoclasts and involved in the regulation of cell differentiation and activation. ligand for RANK that is presented/secreted by osteocytes, osteoblasts, and other cells (such as bone-marrow adipocytes). RANKL binds to and activates RANK. a key transcription factor in the differentiation of osteoblast progenitor cells. a truncated recombinant form of human PTH. It contains the first 34 amino acids of the original molecule and is approved as an osteoanabolic drug in the treatment of osteoporosis. a highly conserved signal transduction pathway for auto or paracrine cell–cell communication. In bone, the canonical Wnt signalling pathway has a role in osteoblast differentiation and function. The downstream effector of this pathway is β-catenin.