PTH and PTH-related peptide enhance steroid secretion from
human adrenocortical cells
Giuseppina
Mazzocchi1,
Francesco
Aragona2,
Ludwik
K.
Malendowicz1, and
Gastone G.
Nussdorfer1
1 Section of Anatomy, Department of Human Anatomy and
Physiology and 2 Department of Urology, University of Padua,
I-35121 Padua, Italy
 |
ABSTRACT |
Parathyroid hormone (PTH) and PTH-related
peptide (PTH-RP) are two hypercalcemic hormones that share a common
receptor subtype, the PTH/PTH-RP receptor. PTH and PTH-RP concentration
dependently enhanced basal aldosterone and cortisol secretion from
dispersed human adrenocortical cells, with a maximal effective
concentration (~2-fold increase) of 10
8 M. The
secretagogue effect of 10
8 M PTH or PTH-RP was abolished
by the PTH/PTH-RP receptor antagonist [Leu11,D-Trp12]-PTH-RP-(7-34)-amide
(10
6 M). PTH and PTH-RP (10
8 M) raised cAMP
and inositol-triphosphate release by dispersed adrenocortical cells,
and these effects were blocked by the adenylate cyclase inhibitor
SQ-22536 (10
4 M) and the phospholipase C (PLC) inhibitor
U-73122 (10
5 M), respectively. SQ-22536
(10
4 M) and U-73122 (10
5 M) partially
inhibited aldosterone and cortisol response to 10
8 M PTH
and PTH-RP; when added together, they abolished it. Similar results
were obtained by using the protein kinase (PK)A and PKC inhibitors H-89
and calphostin C (10
5 M). It is concluded that PTH and
PTH-RP exert a sizeable secretagogue action on the human adrenal
cortex, probably acting through the PTH/PTH-RP receptor coupled with
both adenylate cyclase/PKA- and PLC/PKC-dependent signaling cascades.
aldosterone; cortisol; protein kinases A and C
 |
INTRODUCTION |
PARATHYROID HORMONE
(PTH) and PTH-related peptide (PTH-RP) are two hypercalcemic hormones
encoded by different genes, which possess similar intron-exon
organization and are thought to have a common ancestral origin. Human
PTH and PTH-RP display a remarkable homology in their amino acid
composition (17) and share a common receptor subtype,
called the PTH/PTH-RP receptor (22).
PTH and PTH-RP are included in the vasoactive intestinal peptide
(VIP)-secretin-glucagon family of peptides, members of which (e.g., VIP
and pituitary adenylate cyclase-activating peptide) are well known to
modulate secretory activity of the adrenal cortex, acting in a
paracrine manner (for a review, see Ref. 16). Accordingly, PTH-RP immunoreactivity has been detected in the cortex of the adult
human adrenal gland (10) and in the adrenal cortex and medulla of human fetuses between the ages of 8 and 40 wk (2, 12). PTH-binding sites have been autoradiographically localized in the rat adrenal cortex (8), and the presence of
PTH/PTH-RP receptor mRNA has been demonstrated in the adrenal gland of
this species (24). A secretagogue action of PTH on
dispersed rat (19, 20), mice (6), and bovine
adrenocortical cells (8, 20) has been reported, but the
possible effect of PTH-RP has not yet been studied. Moreover, no
investigations were carried out using dispersed human adrenocortical cells.
Here we report findings strongly suggesting that both PTH and PTH-RP
enhance steroid hormone secretion from human adrenocortical cells,
through a common signaling mechanism involving the activation of both
adenylate cyclase/protein kinase (PK)A and phospholipase C (PLC)/PKC cascades.
 |
MATERIALS AND METHODS |
Reagents.
Human PTH and PTH-RP, adrenocorticotropic hormone (ACTH), angiotensin
II, and corticotropin-inhibiting peptide (CIP) were purchased from
Peninsula Laboratories (St. Helens, UK). SQ-22536, U-73122, H-89, and
calphostin C were obtained from Biomol Research Laboratories (DBA,
Milan, Italy). Human
[Leu11,D-Trp12]PTH-RP-(7-34)-amide
was provided by Phoenix Pharmaceutical (Belmont, CA). Appropriate
references for the effects of the above mentioned chemicals can be
found in the catalogs of the purchasers. Medium 199 was obtained from
Difco (Detroit, MI), and IBMX, human serum albumin (HSA), and other
laboratory reagents were provided by Sigma Chemical (St. Louis, MO).
RIA kits for aldosterone and cortisol were purchased from IRE-Sorin
(Vercelli, Italy), and RIA kits for cAMP and
D-myo-inositol-1,4,5-triphosphate
(IP3) were obtained from Amersham Pharmacia (Aylesbury, UK).
Dispersed human adrenocortical cells.
Dispersed cells were obtained from adrenal glands removed from 16 consenting patients undergoing unilateral nephrectomy with ipsilateral
adrenalectomy for renal cancer. Starting from 2 wk before surgery,
patients were kept on a normal diet; only patients not requiring
medications to alter adrenal function were recruited. Adrenal tails,
which do not contain medullary chromaffin tissue (14),
were collected immediately after excision in the operating room, placed
in Krebs-Ringer bicarbonate buffer with 0.2% glucose at 4°C, and
immediately carried to our laboratory, where cell isolation was
performed by sequential collagenase digestion and mechanical
disaggregation. Our adrenocortical cell preparations were a mixture of
zona glomerulosa (ZG) and zona fasciculata-reticularis (ZF/R) cells,
and their contamination by stromal elements, as evaluated by phase
microscopy, was virtually absent. The viability of isolated cells, as
checked by the trypan blue exclusion test, was >90%. Adjacent
sections of the adrenal glands underwent pathological evaluation and
were found to be histologically normal. The study protocol was approved
by the Padua Ethical Committee for Human Studies.
Steroid hormone secretion.
Dispersed cells were put in medium 199 and Krebs-Ringer bicarbonate
buffer with 2% glucose containing 5 mg/ml HSA and were incubated
(105 cells/ml, in replicates of three each). The following
incubation experiments were performed: 1) PTH or PTH-RP
(from 10
12 to 10
6 M); 2) PTH or
PTH-RP (10
8 M) and ACTH or ANG II (10
9 M)
alone or in the presence of 10
6 M
[Leu11,D-Trp12]PTH-RP-(7-34)-amide;
3) ACTH (10
9 M) and PTH or PTH-RP
(10
8 M) alone or in the presence of 10
6 M
CIP; 4) PTH or PTH-RP (10
8 M) alone or in the
presence of 10
4 M SQ-22536 and/or 10
5 M
U-73122; and 5) PTH or PTH-RP (10
8 M) alone or
in the presence of 10
5 M H-89 and/or calphostin C. Incubations were carried out in a shaking bath at 37°C for 90 min in
an atmosphere of 95% air-5% CO2, as previously described
(14). The medium was collected and kept frozen at
80°C
until hormonal assays. Aldosterone and cortisol were extracted from
incubation media and purified by HPLC (14). Their
concentrations were measured by RIA, with the ALDO-CTK2 (sensitivity, 5 pg/ml; intra- and interassay variations, 7.3 and 8.4%) and cortisol
RIA (sensitivity, 30 pg/ml; intra- and interassay variations, 6.0 and
7.5%) kits.
cAMP and IP3 production.
Dispersed cells were incubated, as described above, for 10 min with PTH
or PTH-RP (10
8 M) alone or in the presence of
10
4 M SQ-22536 or 10
5 M U-73122. In the
case of cAMP assay, the phosphodiesterase inhibitor IBMX
(10
4 M) was added to prevent cAMP metabolism. cAMP was
extracted by incubating the medium with 0.1 N HCl for 20 min at 4°C.
The HCl extract was then neutralized, and cAMP concentration was
determined by following the protocol of the Amersham Biotrak TRK 432 (sensitivity, 1 pmol/l; intra- and interassay variations, 5.3 and
6.6%). IP3 was extracted by the trichloroacetic acid
method and purified by Amprep SAX-minicolumn chromatography, and its
concentration was measured by RIA. The procedure followed the protocol
of the Amersham Biotrak TRK 1000 (sensitivity, 2 pmol/l; intra- and
interassay variations, 6.8 and 8.1%).
Statistics.
Each incubation experiment was performed in quadruplicate by use of
dispersed cells obtained from four different adrenal glands. Data
obtained from each adrenal were averaged and expressed as the
means ± SE of four separate experiments. The statistical
comparison of results was performed using ANOVA, followed by the
Duncan's Multiple Range Test. A value of P < 0.05 was
considered significant.
 |
RESULTS |
PTH and PTH-RP concentration dependently increased basal secretion
of both aldosterone and cortisol from dispersed cells, minimal and
maximal effective concentrations being 10
10 M and
10
8 M (Fig. 1). The potency
(EC50) and efficacy (percent increase elicited by the
maximal effective concentration) of PTH were slightly but significantly
less than those of PTH-RP [(PTH vs. PTH-RP) for aldosterone:
EC50, 1.1 ± 0.2 × 10
10 M vs.
2.3 ± 0.4 × 10
10 M (P < 0.02; n = 4); efficacy, 91 ± 8 vs. 137 ± 12% (P < 0.01; n = 4); for cortisol:
EC50, 5.6 ± 0.6 × 10
10 M vs.
1.8 ± 0.3 × 10
10 M (P < 0.01; n = 4); efficacy, 97 ± 6 vs. 122 ± 9% (P < 0.05 ; n = 4)].

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Fig. 1.
Effects of parathyroid hormone (PTH, A) and
PTH-related peptide (RP, B) on aldosterone and cortisol
secretion from dispersed human adrenocortical cells. Data, expressed as
pmol · 106
cells 1 · h 1, are means ± SE
of 4 separate experiments. +P < 0.05 and
*P < 0.01 vs. respective baseline (B)
value.
|
|
CIP (10
6 M) abolished the secretory response of dispersed
adrenocortical cells to 10
9 M ACTH (Fig.
2) but did not alter the response to
10
8 M PTH or PTH-RP (Fig.
3). Conversely, the secretagogue effect of PTH and PTH-RP was annulled by 10
6 M
[Leu11,D-Trp12]PTH-RP
(7-34)-amide (Fig. 3), which was unable to affect the response to 10
9 M ACTH or ANG II (data not shown).

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Fig. 2.
Effect of corticotropin-inhibitin peptide (CIP;
10 6 M) on 10 9 M ACTH-stimulated aldosterone
and cortisol secretion from dispersed human adrenocortical cells. Data,
expressed as pmol · 106
cells 1 · h 1, are means ± SE
of 4 separate experiments. *P < 0.01 vs. respective
baseline value (B); AP < 0.01 vs.
respective control value.
|
|

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Fig. 3.
Effects of CIP (10 6 M) and the PTH/PTH-RP
receptor antagonist (A)
[Leu11,D-Trp12]PTH-RP-(7-34)-amide
(10 6 M) on PTH- or PTH-RP (10 8
M)-stimulated aldosterone (top) and cortisol secretion
(bottom) from dispersed human adrenocortical cells. Data,
expressed as pmol · 106
cells 1 · h 1, are means ± SE
of 4 separate experiments. *P < 0.01 vs. respective
baseline value (B); AP < 0.01 vs.
respective control value.
|
|
PTH and PTH-RP (10
8 M) evoked 3.0- to 3.5-fold rises in
cAMP and IP3 release by dispersed adrenocortical cells
(Fig. 4). cAMP response was blocked by
10
4 M SQ-22536, and IP3 response was annulled
by 10
5 M U-73122 (Fig. 4). SQ-22536 (10
4 M)
and U-73122 (10
5 M) partially inhibited the stimulating
effect of 10
8 M PTH or PTH-RP on both aldosterone and
cortisol secretion, and when added together they abolished it (Fig.
5). Similar results were obtained by
using H-89 (10
5 M) and calphostin C
(10
5 M; Fig. 6). These
inhibitors did not affect basal hormonal production (Figs. 5 and 6).

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Fig. 4.
Effects of PTH and PTH-RP (10 8 M) on cAMP
(top) and
D-myo-inositol-1,4,5-triphosphate
(IP3) production (bottom) from dispersed human
adrenocortical cells, and their reversal by SQ-22536 (10 4
M) and U-73122 (10 5 M), respectively. Data, expressed as
pmol · 106
cells 1 · min 1, are means ± SE
of 4 separate experiments. *P < 0.01 vs. respective
baseline value (B); AP < 0.01 vs.
respective control value.
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|

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Fig. 5.
Effects of SQ-22536 (10 4 M) and/or U-73122
(10 5 M) on 10 8 M PTH or PTH-RP-stimulated
aldosterone (top) and cortisol secretion (bottom)
from dispersed human adrenocortical cells. Data, expressed as
pmol · 106
cells 1 · h 1, are means ± SE
of 4 separate experiments. +P < 0.05 and
*P < 0.01 vs. respective baseline value (B);
aP < 0.05 and
AP < 0.01 vs. respective control value.
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Fig. 6.
Effects of calphostin C (10 5 M) and/or H-89
(10 5 M) on 10 8 M PTH- or PTH-RP-stimulated
aldosterone (top) and cortisol secretion (bottom)
from dispersed human adrenocortical cells. Data, expressed as
pmol · 106
cells 1 · h 1, are means ± SE
of 4 separate experiments. +P < 0.05 and
*P < 0.01 vs. respective baseline value (B);
aP < 0.05 and
AP < 0.01 vs. respective control value.
|
|
 |
DISCUSSION |
Our present findings show that PTH and PTH-RP exert a sizeable
stimulatory action on basal steroid hormone secretion from human
adrenocortical cells. The similarity of the effects of the two peptides
strongly suggests that they act through a common receptor, the
PTH/PTH-RP receptor (22). This contention is supported by
the demonstration that the PTH/PTH-RP receptor antagonist
[Leu11,D-Trp12]PTH-RP-(7-34)-amide
abolished the secretory response of dispersed adrenocortical cells to
both PTH and PTH-RP. Conceivably, both ZG and ZF/R cells are provided
with this receptor, inasmuch as both aldosterone and cortisol
production are enhanced. The biologically active region of PTH (the
1-34 sequence) displays a remarkable homology with that of
ACTH-(1-39) (18). However, the
possibility that PTH and PTH-RP may interfere with the receptors of
ACTH, the most potent in vitro stimulator of both aldosterone and
cortisol (for review, see Ref. 26), is unlikely because
the ACTH-receptor antagonist CIP, at a concentration annulling the
secretagogue action of the maximal effective concentration of ACTH,
does not affect the secretory response to PTH and PTH-RP. The slightly minor effectiveness of PTH, compared with PTH-RP, in eliciting a
secretory response by human adrenocortical cells may be explained by a
lower affinity for PTH/PTH-RP receptors. This possibility, although
requiring confirmation, appears to be in keeping with the fact that PTH
binds not only PTH/PTH-RP receptors but also PTH2 and C-PTH
receptors, whereas PTH-RP is selective for PTH/PTH-RP receptors
(7, 22, 25).
Evidence indicates that PTH/PTH-RP receptors, by coupling to multiple G
proteins, activate adenylate cyclase and PLC cascades (21). Our present findings clearly indicate that both PTH
and PTH-RP stimulate basal steroid secretion from dispersed human adrenocortical cells through both adenylate cyclase/PKA- and
PLC/PKC-dependent signaling mechanisms. In fact, 1) PTH and
PTH-RP markedly raise cAMP and IP3 production by dispersed
adrenocortical cells; 2) the secretagogue effect of PTH and
PTH-RP is partially suppressed by either the adenylate cyclase
inhibitor SQ-22536 or the PLC inhibitor U-73122 at concentrations able
to abolish cAMP and IP3 responses of adrenocortical cells
to both hormones, and it is annulled by the simultaneous exposure to
the two inhibitors; 3) the PKA inhibitor H-89 and the PKC
inhibitor calphostin C elicited suppressive effects similar to those of
SQ-22536 and U-73122; and 4) as previously shown
(11), none of these inhibitors induces significant changes
in the basal steroid secretion over 90 min of static incubation, which
lessens the likelihood that their effect may be due to a nonspecific
toxic lesion of the steroidogenic machinery.
The possible role of the stimulating effect of PTH and PTH-RP in the
physiological regulation of the human adrenal gland remains to be
demonstrated. However, we wish to mention some pathological conditions
in which our findings may become relevant. First, the aldosterone and
cortisol secretagogue effect of PTH and PTH-RP could, at least in part,
explain the mild hypertension frequently associated with primary
hyperparathyroidism (for review, see Ref. 5). Second, PTH
and PTH-RP were found to be highly expressed in an adrenal carcinoma
producing pseudohyperparathyroidism and Cushing's syndrome
(3). Finally, elevated serum concentrations of PTH and
PTH-RP were observed in several patients bearing benign or malignant
pheochromocytomas (1, 4, 13, 23), and PTH-RP mRNA was
detected in several benign tumors (9, 13). The association of secreting pheochromocytomas with adrenocortical tumors and idiopathic hypercorticism has been described (for review, see Ref.
15), and our study could provide a clue to explain these observations.
 |
FOOTNOTES |
Address for reprint requests and other correspondence: G. G. Nussdorfer, Dept. of Human Anatomy and Physiology, Section of Anatomy, Via Gabelli 65, I-35121 Padova, Italy (E-mail:
ggnanat{at}ipdunidx.unipd.it).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8 May 2000; accepted in final form 5 October 2000.
 |
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Am J Physiol Endocrinol Metab 280(2):E209-E213
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