Bcl-2 lies downstream of parathyroid hormone-related peptide in a signaling pathway that regulates chondrocyte maturation during skeletal development.

Parathyroid hormone-related peptide (PTHrP) appears to play a major role in skeletal development. Targeted disruption of the PTHrP gene in mice causes skeletal dysplasia with accelerated chondrocyte maturation (Amizuka, N., H. Warshawsky, J.E. Henderson, D. Goltzman, and A.C. Karaplis. 1994. J. Cell Biol. 126:1611-1623; Karaplis, A.C., A. Luz, J. Glowacki, R.T. Bronson, V.L.J. Tybulewicz, H.M. Kronenberg, and R.C. Mulligan. 1994. Genes Dev. 8: 277-289). A constitutively active mutant PTH/PTHrP receptor has been found in Jansen-type human metaphyseal chondrodysplasia, a disease characterized by delayed skeletal maturation (Schipani, E., K. Kruse, and H. Jüppner. 1995. Science (Wash. DC). 268:98-100). The molecular mechanisms by which PTHrP affects this developmental program remain, however, poorly understood. We report here that PTHrP increases the expression of Bcl-2, a protein that controls programmed cell death in several cell types, in growth plate chondrocytes both in vitro and in vivo, leading to delays in their maturation towards hypertrophy and apoptotic cell death. Consequently, overexpression of PTHrP under the control of the collagen II promoter in transgenic mice resulted in marked delays in skeletal development. As anticipated from these results, deletion of the gene encoding Bcl-2 leads to accelerated maturation of chondrocytes and shortening of long bones. Thus, Bcl-2 lies downstream of PTHrP in a pathway that controls chondrocyte maturation and skeletal development.

A parathyroid hormone-like protein from cultured human keratinocytes.

Parathyroid hormone-like factors have been found in extracts of tumors associated with humoral hypercalcemia of malignancy, many of which are of squamous epithelial origin. Cultured, nonmalignant human keratinocytes were examined for the production of similar factors. Keratinocyte-conditioned medium from ten cultures stimulated the production of cyclic adenosine monophosphate in clonally derived rat osteosarcoma cells sensitive to parathyroid hormone. Bovine [Nle8,18, Tyr34]PTH-(3-34)NH2, a competitive inhibitor of parathyroid hormone, stopped the adenylate cyclase production stimulated by keratinocyte-conditioned medium, but antisera to parathyroid hormone had no effect on such adenylate cyclase activity. The active component of keratinocyte-conditioned medium has a molecular weight exceeding that of native parathyroid hormone. These characteristics are shared by the parathyroid hormone receptor agonists associated with humoral hypercalcemia of malignancy, which suggests that normal human keratinocytes may produce a factor related to that produced by malignant tumors associated with humoral hypercalcemia of malignancy.

Impaired phosphorus conservation and 1,25 dihydroxyvitamin D generation during phosphorus deprivation in familial hypophosphatemic rickets.

The pathogenesis of familial hypophosphatemic rickets (FHR) is incompletely understood. We therefore examined the effects of acute dietary phosphorus deprivation to see whether renal phosphate conservation and increased 1,25 dihydroxyvitamin D [1,25(OH)2D] plasma levels, which normally follow restriction of phosphorus intake, could be induced in patients with FHR. Six healthy male volunteers (age 26 +/- 3 yr) and seven male patients with FHR (age 24 +/- 3 yr) were placed on a low phosphorus diet supplemented with aluminum hydroxide and studied over a 4-d period. The patients with FHR excreted more than five times as much phosphorus per day at the conclusion of the study than did the controls (176 +/- 61 mg/24 h vs. 33 +/- 11 mg/h). In the normal subjects, maximum tubular reabsorptive capacity for phosphorus/glomerular filtration rate (TmP/GFR) rose progressively during phosphorus deprivation, and the rise from base line was more than two times greater than that seen in patients with FHR. Immunoreactive parathyroid hormone levels and nephrogenous cyclic AMP were initially normal in both groups and no change was seen in either group with phosphorus deprivation. In the normal subjects, 1,25(OH)2D levels rose progressively over the 96 h of the study (49 +/- 3 to 63 +/- 6 pg/ml, P less than 0.05), while mean circulating 1,25(OH)2D in the patients with FHR did not change (34 +/- 3 to 29 +/- 3 pg/ml). The changes in individual plasma 1,25(OH)2D levels correlated strongly with the change in individual nephrogenous cyclic AMP measurements in the patients with FHR (r = +0.93), while no such correlation was observed in the normal subjects. These data demonstrate a defective renal response to phosphorus deprivation in patients with FHR including a qualitatively abnormal response in 1,25(OH)2D generation.

Nephrogenous cyclic adenosine monophosphate as a parathyroid function test.

Nephrogenous cyclic AMP (NcAMP), total cyclic AMP excretion (UcAMP), and plasma immunoreactive parathyroid hormone (iPTH), determined with a multivalent antiserum, were prospectively measured in 55 control subjects, 57 patients with primary hyperparathyroidism (1 degrees HPT), and 10 patients with chronic hypoparathyroidism. In the group with 1 degrees HPT, NcAMP was elevated in 52 patients (91%), and similar elevations were noted in subgroups of 26 patients with mild (serum calcium

Effects of catecholamines and adrenergic-blocking agents on plasma and urinary cyclic nucleotides in man.

Studies were performed in healthy volunteers to determine the effects of catecholamines and adrenergic-blocking agents on plasma and urinary levels of adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP). Plasma cyclic AMP rose in response to infusions of the beta-adrenergic agent, isoproterenol, or in response to infusions of either epinephrine or norepinephrine alone or in combination with the alpha-adrenergic-blocking agent, phentolamine. Although urinary cyclic AMP also rose, the percentage increase was less than that observed in the plasma. These treatments caused no increase in plasma cyclic GMP. Plasma cyclic GMP rose in response to infusions of alpha-adrenergic agents, viz., epinephrine or norepinephrine infused together with the beta-blocking agent, propranolol. These treatments caused no increase in plasma cyclic AMP. These observations are consistent with the current concept that the actions of beta-adrenergic agents are mediated by increases in cyclic AMP formation in target tissues. Such a mediating role has not been established for cyclic GMP, but the data suggest the possibility that cyclic GMP metabolism is responsive either to alpha-adrenergic stimulation or to parasympathetic stimulation which occurs as a reflexive consequence of the pressor effect of alpha-adrenergic agents.

Kinetic parameters and renal clearances of plasma adenosine 3',5'-monophosphate and guanosine 3',5'-monophosphate in man.

Kinetic parameters and the renal clearances of plasma adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP) were evaluated in normal subjects using tritium-labeled cyclic nucleotides. Each tracer was administered both by single, rapid intravenous injection and by constant intravenous infusion, and the specific activities of the cyclic nucleotides in plasma and urine were determined. Both cyclic AMP and cyclic GMP were cleared from plasma by glomerular filtration. The kidney was found to add a variable quantity of endogenous cyclic AMP to the tubular urine, amounting to an average of approximately one-third of the total level of cyclic AMP excreted. Plasma was the source of virtually all of the cyclic GMP excreted. Plasma levels of the cyclic nucleotides appeared to be in dynamic steady state. The apparent volumes of distribution of both nucleotides exceeded extracellular fluid volume, averaging 27 and 38% of body weight for cyclic AMP and cyclic GMP, respectively. Plasma production rates ranged from 9 to 17 nmoles/min for cyclic AMP and from 7 to 13 nmoles/min for cyclic GMP. Plasma clearance rates averaged 668 ml/min for cyclic AMP and 855 ml/min for cyclic GMP. Approximately 85% of the elimination of the cyclic nucleotides from the circulation was due to extrarenal clearance.

Effects of glucagon on adenosine 3',5'-monophosphate and guanosine 3',5'-monophosphate in human plasma and urine.

Glucagon, infused intravenously into fasting, well-hydrated, normal men in doses of 25-200 ng/kg per min, induced up to 30-fold increases in both plasma and urinary cyclic AMP. Cyclic GMP levels were unaffected by glucagon. Simultaneous cyclic AMP and inulin clearance studies demonstrated that the glucagon-induced increase in urinary cyclic AMP was entirely due to glomerular filtration of the elevated plasma levels of the nucleotide. The cyclic AMP response to glucagon was not mediated by parathyroid hormone or epinephrine, and trypsintreated glucagon was completely inactive. The perfused rat liver released cyclic AMP into the perfusate in response to glucagon, indicating that the liver is a possible source of the cyclic AMP entering the extracellular fluids in response to glucagon in vivo.

In vitro adenylate cyclase-stimulating activity predicts the occurrence of humoral hypercalcemia of malignancy in nude mice.

A number of factors have been proposed as potential mediators of the syndrome of humoral hypercalcemia of malignancy (HHM), but to date no firm cause-and-effect relationship has been established. We attempted to establish such a relationship by determining whether the presence or absence of adenylate cyclase-stimulating activity (ACSA) in the media of cultured tumor cells predicted the occurrence of the syndrome of HHM when these cell lines were grown in nude mice in vivo. Conditioned media from 35 human renal carcinoma cell lines were surveyed for ACSA in the PTH-sensitive rat osteosarcoma 17/2.8 cell assay. 12 lines were positive (mean, 13.7-fold stimulation, range, 3.0 to 44.0), and 23 lines were negative (mean, 1.2-fold stimulation, range, 0.9 to 1.5). We were successful in establishing five of the positive and six of the negative lines in three to five nude mice per line. Mice implanted with the positive lines uniformly became hypercalcemic (mean serum calcium, 15.8 mg/dl), whereas mice implanted with the negative lines uniformly remained normocalcemic (mean serum calcium, 9.5 mg/dl), in spite of comparable mean tumor size. Acid-urea tumor extracts from each of four hypercalcemic animals contained potent in vitro ACSA (mean, 15.9-fold stimulation), while 5/5 extracts from normocalcemic animals did not (mean, 1.4-fold stimulation). Our study demonstrates that in this model system in vitro ACSA is a reliable predictive marker for HHM in vivo. Whether the protein responsible for this activity is also the mediator of the bone resorption seen in HHM remains to be demonstrated.

Synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats.

Parathyroid hormone-like adenylate cyclase-stimulating proteins (hACSPs) have been implicated as one of the calcemic, bone-resorbing agents in patients with humoral hypercalcemia of malignancy. We report the synthesis of an amino-terminal hACSP fragment, Tyr36 hACSP (1-36) amide. The synthetic hACSP is a potent agonist of renal membrane adenylate cyclase (Km, 1.7 X 10(-10)) and of bone cell adenylate cyclase (Km 1 X 10(-9)M). It is a potent bone-resorbing agent in vitro, stimulating 45Ca release from fetal rat long bones at a concentration of 10(-9) M. When infused via osmotic minipumps into rats, it is also a potent calcemic factor in vivo, inducing a rise in serum calcium from (mean +/- SD) 10.6 +/- 0.6 to 19.7 +/- 3.2 mg/dl when infused at 1.4 micrograms/h and from 9.9 +/- 0.7 to 11.4 +/- 1.2 mg/dl when infused at 0.14 micrograms/h. These findings indicate that biologically active hACSP fragments can be synthesized. One such synthetic peptide possesses the in vitro and in vivo bioactivities demonstrated in native, tumor-derived hACSPs. It is also a potent calcemic, bone-resorbing agent.

Effects of parathyroid hormone on plasma and urinary adenosine 3',5'-monophosphate in man.

The effects of parathyroid hormone (PTH) on plasma and urinary adenosine 3',5'-monophosphate (cyclic AMP) levels were studied in normal subjects. Under basal conditions normal adults have plasma concentrations of cyclic AMP ranging from 10 to 25 nmoles/liter and excrete from 1.5 to 5 mumoles of cyclic AMP per g of urinary creatinine. About one-half to two-thirds of the cyclic AMP excreted in the urine is derived from the plasma by glomerular filtration, and the remainder is produced by the kidney. Renal production of cyclic AMP is partly under the control of PTH. It can be suppressed by infusions of calcium and stimulated by infusions of the calcium chelating agent, EDTA. Infusions of PTH in doses up to 10 mU/kg per min were associated with dose-related increases both in urinary cyclic AMP and phosphate. Infusions of PTH in doses ranging from 20 to 80 mU/kg per min did not lead to any further increase in phosphaturia but did lead to further marked increases in urinary cyclic AMP. A modest increase in plasma cyclic AMP was noted when PTH was infused at 40 mU/kg per min. Anephric patients failed to show appreciable increases in plasma cyclic AMP in response to large doses of PTH but did show expected increases in response to glucagon. Surgical removal of parathyroid adenomas from nine patients with primary hyperparathyroidism was invariably followed by a decrease in urinary cyclic AMP, PTH, in large doses, and calcium infusion produced up to 2-fold increases in the other known naturally occurring cyclic nucleotide, guanosine 3',5'-monophosphate (cyclic GMP).

Identification of transcripts encoding a parathyroid hormone-like peptide in messenger RNAs from a variety of human and animal tumors associated with humoral hypercalcemia of malignancy.

The syndrome of humoral hypercalcemia of malignancy (HHM) appears to be mediated in many instances by a parathyroid hormone-like peptide, which has recently been purified, sequenced, and cloned. Using a probe representing the coding region of the human PTH-like peptide, we examined by Northern analysis poly (A)+ RNA from a variety of human and animal tumors associated with HHM. Hybridizing transcripts were identified in mRNA from each of 12 human and each of four animal HHM-associated tumors, with a complex hybridization pattern observed in the human mRNAs and a relatively simple pattern observed in the animal mRNAs. Poly (A)+ RNA prepared from tumors of similar histological types unassociated with HHM failed to hybridize with the probe. Messenger RNA-dependent biological activity from the animal tumors was entirely eliminated in a hybridization-arrest experiment using a complementary oligonucleotide spanning the region of homology between human PTH and the PTH-like peptide. These findings indicate that the PTH-like peptide is associated with the syndrome of HHM in a wide spectrum of tumor types from a variety of mammalian species and that the PTH-like sequence in the proximal amino terminus of the peptide is highly conserved.

Factors associated with humoral hypercalcemia of malignancy stimulate adenylate cyclase in osteoblastic cells.

The culture media of three cell lines, a human prostate carcinoma (PC3), a rat Leydig cell tumor (Rice-500), and a rat carcinosarcoma (WRC-256), that were derived from tumors associated with humoral hypercalcemia of malignancy (HHM), were examined for stimulation of adenylate cyclase in ROS 17/2.8 osteoblastic cells and for bone resorptive activity in culture. Cells from a nonhypercalcemic variant of the WRC256 tumor served as control. Extracts from three solid human tumors, a lung adenocarcinoma from a patient with HHM and two adenocarcinoma from normocalcemic patients (lung and colon), were also examined for adenylate cyclase stimulation. We found excellent correlation between stimulation of cyclic AMP accumulation in ROS 17/2.8 cells and bone resorbing activity in culture, or production of HHM in vivo. Stimulation of adenylate cyclase by HHM factors was inhibited by the parathyroid hormone competitive inhibitor, [8norleucyl, 18norleucyl, 34tyrosinyl] bovine parathyroid hormone (3-34) amide.

Parathyroid hormone-related protein gene expression in human squamous carcinoma cells is repressed by mutant isoforms of p53.

Parathyroid hormone-related protein (PTHrP) is a normal secretory product of a variety of squamous epithelia, including epidermal keratinocytes. Only a subset of squamous carcinomas, however, express the gene at levels sufficient to cause humoral hypercalcemia. In the present study, comparison of PTHrP expression levels with p53 functional status in a series of squamous carcinoma lines has revealed an association between expression of specific mutant isoforms of p53 and very low levels of PTHrP mRNA. Evaluation of p53 isoforms with mutations in codons 248 and 273 showed them to be capable of repressing PTHrP gene expression in a high-expressing, p53-negative squamous line by approximately 50%. Conversely, inactivation of an endogenous mutant p53 with E1B proteins resulted in an increase in PTHrP expression in a low-expressing cell line. Subsequent analysis of promoter-specific PTHrP transcripts in a p53-negative squamous line transfected with mutant p53 isoforms suggested that down-regulation occurred primarily at the two TATA-based promoters. Direct testing of a murine PTHrP reporter construct in transient transfection assays confirmed the capacity of the 248 and 273 mutants to repress this TATA-based promoter, although only about half as effectively as wild-type p53.

Transactivation of the PTHrP gene in squamous carcinomas predicts the occurrence of hypercalcemia in athymic mice.

Humoral hypercalcemia of malignancy (HHM) is caused by the secretion of parathyroid hormone-related protein (PTHrP) by tumor cells, and tumors of squamous histology are the ones most commonly complicated by HHM. To determine why some squamous tumors cause HHM and others do not, we quantitated the levels of PTHrP mRNA expression and PTHrP secretion in a series of eight squamous tumor lines. As anticipated, we found that the level of PTHrP mRNA expression in individual lines correlated with their PTHrP secretion rates. However, PTHrP mRNA levels varied widely in individual lines, and only those tumor lines with the highest levels of PTHrP gene expression were able to cause hypercalcemia in athymic mice. We found that a specific segment of the PTHrP promoter could reproduce the relative pattern of PTHrP gene expression when cloned in front of a chloramphenicol acetyltransferase reporter gene and transiently transfected into these squamous lines. Deletional analysis confirmed that specific sequences within the PTHrP gene promoter appeared to be involved in the transactivation of the gene in tumor lines expressing high levels of PTHrP mRNA. These data suggest that the ability of a given squamous tumor to cause HHM is ultimately a function of its level of PTHrP gene expression, which in turn appears to be a function of the ability of specific transcription factors to transactivate PTHrP gene expression.

Identification of an up-stream promoter of the human parathyroid hormone-related peptide gene.

Previous evidence has suggested that the human PTH-related peptide (PTHRP) gene uses two promoters, one a short down-stream element lying immediately between two 5' exons (1 and 2) and a second lying in an unknown up-stream location. We approached identification of the up-stream element in three steps. First, Northern analysis carried out using progressively 5' fragments of the gene as probes identified a candidate region some 2.5 kilobases up-stream of exon 1. Second, a battery of overlapping 5' cRNA probes was used in RNase protection experiments to identify two previously unrecognized exons, 212 and 93 basepairs in length (termed exons 1A and 1B to distinguish them from the previously designated exon 1, which was termed exon 1C). Third, primer extension experiments were performed with oligonucleotides complementary to each of the 5' exonic sequences. These experiments identified a transcription start site up-stream of exon 1A and also demonstrated that the 5' exons of the PTHRP gene could be spliced together in several combinations. The up-stream promoter element contains a TATA box, but does not otherwise resemble the down-stream PTHRP gene promoter or the PTH gene promoter. We conclude that the human PTHRP gene contains eight exons spanning more than 15 kilobases of genomic DNA, with promoter elements lying immediately up-stream of exons 1A and 2. The identification of these elements will permit functional analysis of their roles in mediating tissue- and tumor-specific PTHRP gene expression.

The parathyroid hormone-related protein associated with malignancy is secreted by neuroendocrine tumors.

We have demonstrated the production of the PTH-related protein (PTHrP) associated with hypercalcemia of malignancy by human neuroendocrine cell lines that also produce calcitonin gene products and chromogranin A. PTHrP was demonstrable in the cells by immunocytochemistry and immunoassay and Northern analysis of the cells revealed the presence of multiple mRNAs for PTHrP. The cell lines also secreted PTHrP in a regulated fashion, with the most potent secretagogue being phorbol. Thus, PTHrP is secreted by neuroendocrine cells and it may have neuroectodermal lineage. The coexpression of calcitonin gene products and chromogranin A, also neuroendocrine, with PTHRP may influence its secretion and ultimate biological effects in vivo.

Identification and characterization of a GC-rich promoter of the human parathyroid hormone-related peptide gene.

The human PTH-related peptide (PTHrP) gene comprises eight exons spanning more than 15 kilobases of genomic DNA. The gene has a highly complex controlling region, which contains four alternatively spliced, noncoding exons and at least two putative promoters, one 5' of exon 1A (up-stream TATA element) and the other 5' of exon 2 (down-stream TATA element). To define important cis regulatory sequences of this gene, a functional dissection of PTHrP 5'-flanking DNA was initiated, using chimeric PTHrP-chloramphenicol acetyltransferase (CAT) constructs. This analysis was carried out in PTHrP-negative human renal carcinoma cells, so that RNA derived from transfected DNA could be studied without interference from endogenous PTHrP sequences. Of the initial series of constructs prepared, the most active was a 1.1-kilobase BamHI-HindIII PTHrP-CAT plasmid containing 350 basepairs of DNA 5' of exon 1C and extending into exon 3. Analysis of transfection products by RNase protection and primer extension revealed that this region contains a previously unrecognized promoter of the gene. This element is located immediately 5' of exon 1C, is active in transfected cells when cloned in isolation up-stream of the CAT gene, and appears to be functional in a number of cell lines and tissues on the basis of primer extension analysis. Unlike the other two PTHrP gene promoters, this element is GC rich and does not possess canonical TATA or CAAT sequences. The human PTHrP gene is one of a handful of genes that appear to use both TATA and GC-rich promoter elements.

Two distinct tumor-derived, parathyroid hormone-like peptides result from alternative ribonucleic acid splicing.

A novel PTH-like peptide has recently been isolated and cloned from human tumors associated with the syndrome of humoral hypercalcemia of malignancy. The deduced product of the initial clones to be reported is a 177 amino-acid protein, consisting of a 36 amino-acid precursor sequence followed by a 141 amino-acid mature peptide. Southern analysis of genomic DNA is compatible with a single-copy gene, but Northern analysis of mRNAs from both tumors and normal tissues consistently reveals multiple hybridizing transcripts, suggesting the possibility of alternative RNA splicing. We provide here direct evidence of alternative RNA splicing by the identification of a second cDNA clone in a human renal carcinoma cDNA library. As compared to the initial clone, this cDNA contains a foreshortened 5'-untranslated region but is otherwise identical until the distal portion of the coding region, at which point it diverges completely to encode a 166 amino-acid mature peptide with 27 amino acids of unique C-terminal sequence. The relative lengths of the primary translation products encoded by these two cDNAs were confirmed by transcription and translation in vitro, and both products were shown to be processed by added microsomes. The unique 3'-ends of these two cDNAs, as well as that of a third cDNA isolated by another laboratory, were used to identify one or more hybridizing transcripts corresponding to each cDNA in mRNA from a human renal carcinoma as well as in mRNA from normal human keratinocytes. We conclude that alternative RNA splicing results in mRNAs which encode multiple PTH-like peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucocorticoid regulation of parathyroid hormone-related peptide gene transcription in a human neuroendocrine cell line.

A PTH-related peptide (PTHRP) has been identified and its cDNA cloned from tumors associated with the syndrome of humoral hypercalcemia of malignancy. The PTHRP and PTH genes appear to represent members of a gene family. Whereas the PTH gene is expressed exclusively in the parathyroids, the PTHRP gene appears to be widely expressed, but little is known concerning the regulation of its expression in any site. We studied the regulation of PTHRP gene expression in a human carcinoid cell line (NCI-H727) which has neuroendocrine features and also produces calcitonin, calcitonin gene-related peptide, and chromogranin-A. We found that the synthetic glucocorticoid triamcinolone produced time- and dose-dependent decreases in steady state PTHRP and calcitonin mRNA levels in NCI-H727 cells. This effect was blocked by the competitive glucocorticoid inhibitor RU-486. Messenger RNA stability and transcription run-off experiments revealed that triamcinolone decreased PTHRP and calcitonin expression by repressing the transcription rates of both genes.

Expression of messenger ribonucleic acids encoding a parathyroid hormone-like peptide in normal human and animal tissues with abnormal expression in human parathyroid adenomas.

A novel PTH-like peptide has recently been purified and cloned from human tumors associated with the syndrome of humoral hypercalcemia of malignancy. We surveyed the expression of mRNAs encoding this peptide in normal tissues by Northern analysis. One or more low abundance hybridizing transcripts was identified in poly(A)+ RNA prepared from human keratinocytes, thyroid, bone marrow, and fibroblasts, from bovine hypothalamus, pituitary, parathyroid, adrenal cortex, and adrenal medulla, and from rat brain, stomach mucosa, and fetal but not adult liver. One or more hybridizing transcripts was also identified in poly(A)+ RNA prepared from a number of established lines, including rat pituitary (GH4), rat pheochromocytoma (PC 12), human osteosarcoma (TE-85), and human medullary carcinoma (TT) cells. Northern analysis of mRNAs from abnormal human parathyroid tissue revealed an overexpression of transcripts for the PTH-like peptide which appeared to be specific for adenomatous or autonomous glands. These findings suggest that the PTH-like peptide is expressed in a number of endocrine and nonendocrine tissues, that it is developmentally expressed in at least one tissue (fetal liver), and that the regulation of its expression is abnormal in human parathyroid adenomas.