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.
Tram
K K
KK
Nephrology Section and Geriatric Research, Veterans Health Administration Medical Center, Sepulveda, California.
Murray
S S
SS
Lee
D B
DB
Murray
E J
EJ
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