Pathogenic mechanisms of glucocorticoid-induced osteoporosis

Glucocorticoids (GCs) belong to the class of steroid hormones that are the most widely prescribed drugs to treat autoimmune and inflammatory disorders for many decades [1], [2]. Since the first two synthetic steroids, metacortandralone and metacortandracin, were approved for clinical trials in 1955 [3], increasing evidence demonstrate that long-term and/or high doses of GCs therapy result in diverse adverse effects, such as type 2 diabetes mellitus and osteoporosis [4].

Glucocorticoid-induced osteoporosis (GIO) is the most common cause of secondary osteoporosis [5], characterized by significant bone loss, decreased bone quality, and increased fracture risk [6], [7], [8]. It is well described that the increase in bone resorption accompanied by the decrease in bone formation occurs during GCs treatment, which could be a major contribution to GIO. Accumulating evidence suggests that he pathogenesis of GIO could be generally attributed to enhanced osteoclastogenesis resultant of the upregulation of macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL) as well as the downregulation of osteoprotegerin (OPG) [9], [10], [11], and to diminished osteoblastogenesis as a result of the inhibition of osteogenesis-related signaling pathways, such as transforming growth factor-beta (TGF-β)/bone morphogenic protein (BMP) and Wnt/β-catenin signaling pathway [12], [13], [14], [15], [16].

It is widely accepted that GCs excess directly affects bone cells, including osteoblasts, osteoclasts, and osteocytes, by interfering with their proliferation, differentiation, apoptosis, and other activities (Fig. 1), which could be critical events in the pathogenesis of GIO. Thus, understanding the potential mechanisms of GCs actions on bone cells is key to better explore therapeutic targets for GIO. The effects of pharmacological GCs on bone cells have been well-reviewed by Hardy [17] and Chotiyarnwong [2]. Here we summarize the timely-update and current research findings regarding the actions of exogenous GCs in bone cells (Table 1) and highlight the crosstalk among them under GC excess (Fig. 2).

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