Osteoblasts secrete transforming growth factor beta (TGF beta) as a biologically inert, latent complex that must be dissociated before the growth factor can exert its effects. We have examined the production and proteolytic activation of latent TGF beta (LTGF beta) by clonal UMR 106-01 rat osteosarcoma cells and neonatal mouse calvarial (MC) osteoblast-like cells in vitro. Synthetic bPTH-(1-34) increased the activity of tissue-type (tPA) and urokinase-type (uPA) plasminogen activators (PA) in cell lysates (CL) of UMR 106-01 cells. The concentration of active TGF beta in serum-free CM from cultures treated with bPTH-(1-34) and plasminogen was significantly greater than in CM from untreated controls and cultures treated with either bPTH-(1-34) or plasminogen alone. This effect occurred at concentrations of PTH-(1-34) that increased PA activity and was prevented by aprotinin, an inhibitor of plasmin activity. Treatment with bPTH-(1-34) had no effect on the concentration of TGF beta in acid-activated samples of CM. Functional consequences of proteolytically activated TGF beta was examined in primary cultures of neonatal MC osteoblast-like cells. Human platelet TGF beta 1 caused a dose-dependent increase in the migration of these cells in an in vitro wound healing assay. Cell migration was also stimulated in cultures treated with bPTH-(1-34) and plasminogen together. This effect was blocked by an anti-TGF beta 1 antibody. The results of these studies demonstrate that (1) LTGF beta secreted by osteoblasts in vitro is activated under conditions where the plasmin activity in the cultures is increased, and (2) the TGF beta generated by plasmin-mediated proteolysis is biologically active. We suggest that the local concentration of TGF beta in bone may be controlled by the osteoblast-associated plasminogen activator/plasmin system. Furthermore, since several calciotropic factors influence osteoblast PA activity, this system may have an important role in mediating their anabolic and/or catabolic effects.

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Bovine parathyroid extract and two commercial preparations containing the first 34 amino acids of synthetic bovine parathyroid hormone [bPTH41-34)] produced dose-related hypotension in anesthetized rats. Dogs were 10 times more sensitive to the two bPTH41-34) preparations than were rats.Propranolol, phentolamine, atropine, and promethazine did not affect the hypotensive action of bPTH-1-34) in rats and dogs. bPTH-1-34) decreased perfusion pressure in rat hindlimbs perfused in situ with Ringer's solution and was a vasodilator in dog kidneys perfused in vitro with Ringer's solution. Helical strips of rabbit aorta were also relaxed by bPTH41-34). We conclude that the direct vasodilatory action of bPTH preparations represents an intrinsic property of parathyroid hormone and that the hypotensive effect of this hormone is produced by part or all of the first NH2-terminal 34 amino acids.The antidiuretic action of exogenous parathyroid preparations in the South American lungfish (Lepidosiren paradoxa) was described in a previous report (1). Because renal function in lungfish is significantly affected by systemic blood pressure (2, 3), we suspected that the antidiuresis resulting from administration of parathyroid extracts might be related to a hypotensive action of this hormone. A vasodilatory action of parathyroid extract and the peptide containing the first 34 amino acids of synthetic bovine parathyroid hormone ] has been reported in dogs (4, 5). This hypotensive action of parathyroid hormone (PTH) has not been confirmed in any other vertebrate species. Furthermore, it was not clear whether the hormone is itself hypotensive or whether its action is mediated through other endogenous vasoactive substances.In a recent series of studies, we observed the vasodepressor actions of synthetic bPTH-(1-34) in the following vertebrates: the South American lungfish, the bullfrog, the water snake Natrix fasciata, and the domestic chicken (6). In the present studies we investigated the specific hypotensive actions of bPTH in the laboratory white rat and the mongrel dog. A dose-related vasodepressor response was demonstrated with two preparations of synthetic bPTH-(1-34). In both rats and dogs, the hypotensive action of bPTH-(1-34) was not inhibited by a-or 3-adrenergic, cholinergic, or histaminergic blocking agents. Furthermore, vasodilation could be demonstrated by using dog kidneys in vitro and rat hindlimbs perfused in situ with mammalian Ringer's solutions. Helical strips of rabbit aorta were also relaxed by bPTH-(1-34). On the basis of these results we propose that mammalian PTH has an intrinsic direct vasodilatory action on the vascular system. The exact mechanism of this action remains to be demonstrated. MATERIALS AND METHODSThree types of experiments were performed. Dogs and rats were used to determine the depressor effect of bPTH preparations in vivo. To test the vasodilatory effects of the synthetic bPTH-(1-34) in vitro, dog kidneys and rabbit aortic strips were perfused. In addition, rat hindlimbs were perfused ...

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