Glucocorticoids maintain human osteoclasts in the active mode of their resorption cycle.
Osteoclasts are known to exert their resorptive activity through a so-called resorption cycle consisting of alternating resorption and migration episodes and resulting typically in the formation of increasing numbers of discrete round excavations on bone slices. This study shows that glucocorticoids deeply modify this resorptive behavior. First, glucocorticoids gradually induce excavations with a trenchlike morphology while reducing the time-dependent increase in excavation numbers. This indicates that glucocorticoids make osteoclasts elongate the excavations they initiated rather than migrating to a new resorption site, as in control conditions. Second, the round excavations in control conditions contain undegraded demineralized collagen as repeatedly reported earlier, whereas the excavations with a trenchlike morphology generated under glucocorticoid exposure appear devoid of leftovers of demineralized collagen. This indicates that collagenolysis proceeds generally at a lower rate than demineralization under control conditions, whereas collagenolysis rates are increased up to the level of demineralization rates in the presence of glucocorticoids. Taking these observations together leads to a model where glucocorticoid-induced increased collagenolysis allows continued contact of osteoclasts with mineral, thereby maintaining resorption uninterrupted by migration episodes and generating resorption trenches. In contrast, accumulation of demineralized collagen, as prevails in controls, acts as a negative-feedback loop, switching resorptive activity off and promoting migration to a new resorption site, thereby generating an additional resorption pit. We conclude that glucocorticoids change the osteoclastic resorption mode from intermittent to continuous and speculate that this change may contribute to the early bone fragilization of glucocorticoid-treated patients.
Søe
Kent
K
Department of Clinical Cell Biology, Vejle Hospital, IRS/CSFU, University of Southern Denmark, Vejle, Denmark. kent.soee@slb.regionsyddanmark.dk
Delaissé
Jean-Marie
JM
D001862:Bone Resorption; D003094:Collagen / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D008855:Microscopy, Electron, Scanning; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure
D005938:Glucocorticoids; D003094:Collagen