PTH-induced osteoblast contraction is mediated by cysteine proteases.
E-64d, a membrane-permeable cysteine protease inhibitor, was tested for its ability to inhibit PTH-induced contraction in intact mouse MC-3T3-E1 osteoblastic cells. Incubation of MC-3T3-E1 cells with vehicle (DMSO) or E-64c, a nonpermeant cysteine protease inhibitor, in the presence or in the absence of PTH had no effects on cAMP production or on morphology from 0 to 90 minutes after addition. In contrast, treatment with E-64d markedly attenuated PTH-induced contraction in these cells. These findings suggest that cysteine proteases, such as the calcium-activated neutral proteases (calpains), are involved in PTH-induced osteoblastic contraction. The observation that cysteine protease activity mediates PTH-induced osteoblastic contraction also suggests that endogenous inhibitors, such as calpastatin, may also be present in the osteoblast and play a role in the regulation of stimulus-response coupling in bone. This mechanism may provide another regulatory point at which bone cells may be pharmacologically manipulated in clinical situations characterized by excessive bone resorption.
Nephrology Section and Geriatric Research, Veterans Health Administration Medical Center, Sepulveda, California.
K K
KK
Tram
S S
SS
Murray
D B
DB
Lee
E J
EJ
Murray
D000818:Animals; D001862:Bone Resorption / Q000503:physiopathology; D002154:Calpain / Q000502:physiology; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D003546:Cysteine Endopeptidases / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010281:Parathyroid Hormone / Q000494:pharmacology* / Q000502:physiology
D015853:Cysteine Proteinase Inhibitors; D010281:Parathyroid Hormone; D000242:Cyclic AMP; D002154:Calpain; D003546:Cysteine Endopeptidases; D007930:Leucine; C108192:aloxistatin