Inhibition of bone resorption in vitro by human enkephalinase (EC 3.4.24.11), a neutral metalloendopeptidase.
Bone metabolism is regulated by a wide variety of both circulating and locally produced peptides. The activity of such agents must be regulated, and one potential regulating mechanism is the inactivation of these peptides by locally produced proteolytic enzymes. One candidate for such a class of enzymes is enkephalinase (EC 2.3.24.11), a membrane-bound neutral metalloendopeptidase that inhibits the activity of a range of biologically active peptides, including interleukin-1 (IL-1), a potent bone-resorbing agent. In this study, we examined the effects of human enkephalinase on bone resorption in cultures of fetal rat long bones. We found that partially purified and highly purified enkephalinase inhibited bone resorption stimulated by parathyroid hormone (PTH) and IL-1 alpha. The effects on PTH-stimulated resorption were reversible, but enkephalinase did not inhibit prestimulated resorption. Enkephalinase also inhibited resorption induced by the nonpeptide stimulators 1,25-(OH)2D3, retinoic acid, and prostaglandin E2 (PGE2). In addition, preliminary studies confirmed a previous report of the presence of an enkephalinase-like activity in osteoblast-like osteosarcoma cells. These data are consistent with the hypothesis that proteolytic enzymes, such as enkephalinase, may play a role in the local regulation of bone resorption.
Ibbotson
K J
KJ
Norwich Eaton Pharmaceuticals Inc., Norwich, New York.
D'Souza
S M
SM
Deschodt-Lanckman
M
M
Appelboom
T E
TE
D000818:Animals; D001862:Bone Resorption / Q000196:embryology / Q000201:enzymology*; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D015260:Neprilysin / Q000302:isolation & purification / Q000494:pharmacology*; D012516:Osteosarcoma / Q000201:enzymology; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors; D051381:Rats; D014407:Tumor Cells, Cultured
D007375:Interleukin-1; D010281:Parathyroid Hormone; D004247:DNA; D015260:Neprilysin