Abstract
Glucocorticoid (GC) therapy is the most frequent cause of secondary osteoporosis. In this study we have demonstrated that GC treatment induced the development of autophagy, preserving osteocyte viability. GC treatment resulted in an increase in autophagy markers and the accumulation of autophagosome vacuoles in vitro and in vivo promoted the onset of the osteocyte autophagy, as determined by expression of autophagy markers in an animal model of GC-induced osteoporosis. An autophagy inhibitor reversed the protective effects of GCs. The effects of GCs on osteocytes were in contrast to tumor necrosis factor α (TNF-α), which induced apoptosis but not autophagy. Together this study reveals a novel mechanism for the effect of GC on osteocytes, shedding new insight into mechanisms responsible for bone loss in patients receiving GC therapy. © 2010 American Society for Bone and Mineral Research.
Highlights
Glucocorticoids (GCs) are used extensively for the treatment of chronic inflammatory and autoimmune diseases
Prolonged use of GCs results in reduction of bone mineral density (BMD), with fractures occurring in 30% to 50% of patients treated chronically with GCs.[1]. Administration of GCs leads to decreased generation of osteoblasts and osteocytes, accompanied by a prolonged lifespan of osteoclasts.[2]. Increased apoptosis of osteocytes and osteoblasts has been observed with high-dose GC treatment in mice and in clinical biopsy specimens in some, but not all, studies.[3,4,5,6] Apoptosis of osteocytes and osteoblasts could reduce bone formation and possibly weaken the bone structure, leading to an increase in fracture risk
Parts of the cytoplasm and intracellular organelles are sequestered within autophagic vacuoles that are eventually delivered to lysosomes for bulk degradation.[10]. Autophagy has been proposed as a ‘‘double-edged sword’’ in heart tissue.[11]. Autophagy can protect the cells from apoptosis by removing oxidatively damaged organelles
Summary
Glucocorticoids (GCs) are used extensively for the treatment of chronic inflammatory and autoimmune diseases. Neither the changes in bone metabolism and bone architecture nor the modest amount of apoptosis of osteoblasts and osteocytes can explain the elevated bone fragility observed in GC-treated patients.[7] We have reported increased osteocyte lacunar size with a loss of perilacunar mineral with GC treatment, suggesting that the osteocyte is metabolically stressed or compromised.[8] In this model of GC treatment, less than 5% of osteocytes were found to be apoptotic, suggesting another effect of GCs. the focus of this study was to determine whether autophagy, a protective mechanism by which cells can respond to stress, may be relevant to GC-induced changes to osteocytes. Whether autophagy is involved in the effect of GCs on bone cells was unknown previously
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