Alternative titles; symbols
HGNC Approved Gene Symbol: PTHLH
Cytogenetic location: 12p11.22 Genomic coordinates (GRCh38): 12:27,958,084-27,972,733 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p11.22 | Brachydactyly, type E2 | 613382 | Autosomal dominant | 3 |
Parathyroid-related protein, signaling through its receptor, PTHR1 (168468), regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. PTHRP is responsible for most cases of humoral hypercalcemia of malignancy.
From the culture medium of a human lung cancer cell line, Moseley et al. (1987) purified a protein with biologic activities similar to those of parathyroid hormone (PTH; 168450). The cancer cells in question contained PTH DNA but no PTH messenger RNA, thus indicating that the PTHR gene is distinct. Suva et al. (1987) and Mangin et al. (1988) identified a cDNA clone that encodes PTHLH. The cDNA encodes a protein of 177 amino acids, containing a precursor sequence of 36 amino acids followed by the mature peptide of 141 amino acids. Eight of the first 13 amino acids in the mature peptide are identical to those of PTH. The sequence diverges completely after amino acid 13, and it is this subsequent region that must account for the distinctive biologic actions of the 2 peptides. Suva et al. (1987) suggested that the PTHL hormone may be important in normal as well as in abnormal calcium metabolism. Karaplis et al. (1994) demonstrated that disruption of the PTHLH gene in murine embryonic stem cells by homologous recombination produced widespread abnormalities of endochondral bone development in mice homozygous for the null mutation. Histologic changes consisted of diminution of chondrocyte proliferation associated with premature maturation of chondrocytes and accelerated bone formation in a pattern consistent with that observed in some chondrodysplasias, particularly the Murk Jansen type of metaphyseal chondrodysplasia (156400).
Yasuda et al. (1989) isolated a single-copy PTHRP gene from a human placental genomic library. They found that the gene spans 13 kb and contains 7 exons. The organization was closely similar to that of the PTH gene, suggesting a common evolutionary origin.
Mangin et al. (1989) isolated and characterized genomic clones encoding the human parathyroid hormone-like peptide gene. The gene contains 6 exons and spans more than 12 kb of DNA. Alternate RNA splicing results in heterogeneity of the mRNA species encoded at the 3-prime ends. Hammonds et al. (1989) reported studies of the 2 forms of PTH: LH1, with 141 amino acids, and another form truncated at its carboxy-terminus, with 108 amino acids.
Mangin et al. (1988) assigned the PTHLH gene to 12p12.1-p11.2 by a combination of Southern analysis of somatic cell hybrid DNA and in situ hybridization. Hendy et al. (1989, 1990) assigned the corresponding gene in the mouse to chromosome 6 by means of Southern blot analysis of DNAs isolated from a panel of mouse/Chinese hamster cell hybrids.
On the basis of studies of the biologic action of PTHRP in cultured human keratinocytes and in SKH-1 hairless mice, Holick et al. (1994) produced strong evidence that PTHRP is an endogenous antiproliferative factor that participates in the regulation of epidermal and hair follicle cell growth. They suggested that the antiproliferative activity of PTH-(1-34), a PTH fragment, and PTHRP-(1-34) may be valuable for treating hyperproliferative skin disorders such as psoriasis. Furthermore, the ability to block the endogenous antiproliferative activity of PTHRP in the skin with an antagonist could be valuable for enhancing epidermal growth in aged skin and during wound healing and for stimulating hair growth.
PTHRP is responsible for most cases of humoral hypercalcemia of malignancy. It mimics the actions of PTH because of its structural homology with PTH and its ability to bind to and signal via the PTH/PTHRP receptor in bone and kidney. PTHRP-(1-36) appears to be one of several secretory forms of PTHRP. When this peptide was given intravenously (iv) to normal volunteers, it produced the same effects as PTH-(1-34). To determine whether PTHRP-(1-36) could be used subcutaneously (sc) in humans as a diagnostic reagent to study differences between HHM and hyperparathyroidism, Henry et al. (1997) examined whether sc PTHRP-(1-36) could affect mineral homeostasis. PTHRP-(1-36) given sc produced increases in circulating PTHRP-(1-36), reductions in serum phosphorus and the renal phosphorus threshold, increments in fractional calcium excretion and nephrogenous cAMP excretion, and increases in plasma 1,25-dihydroxyvitamin D. The authors concluded that it is feasible to use PTHRP-(1-36) in studies of HHM and hyperparathyroidism.
Strewler (2000) reviewed the physiology of parathyroid hormone-related protein. He commented that the breadth of its biologic actions is impressive. PTHLH has evolved to regulate local tissue functions, in contrast to the systemic hormonal function of parathyroid hormone. To carry out its diverse biologic roles, PTHLH functions as a poly-hormone that gives rise to several biologically active peptides, each of which presumably has its own receptor. To broaden its repertoire even further, it appears to have intracrine effects in the nucleus of cells that produce it, in addition to having juxtacrine, paracrine, and possibly endocrine effects after secretion. Strewler (2000) noted that the discovery of PTHLH as the result of the clinical investigation of hypercalcemia in patients with cancer aptly illustrates the adage, 'Medicine is the tutor of biology.'
Studies in transgenic mice demonstrated that PTHRP, signaling through the PTH/PTHRP receptor (PTHR1; 168468), regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth (Wysolmerski et al., 1998; Philbrick et al., 1998). Loss-of-function mutations in the PTHR1 gene result in a rare, lethal form of dwarfism known as Blomstrand chondrodysplasia (215045). These patients suffer from severe defects in endochondral bone formation, but abnormalities in breast and tooth development had not been reported. To ascertain whether PTHRP signaling was important to human breast and tooth development, Wysolmerski et al. (2001) studied 2 fetuses with Blomstrand chondrodysplasia. These fetuses lacked nipples and breasts. Developing teeth were present, but they were severely impacted within the surrounding alveolar bone, leading to distortions in their architecture and orientation. Compatible with the involvement of PTHR1 and PTHRP in human breast and tooth morphogenesis, both were expressed within the developing breasts and teeth of normal human fetuses. The authors concluded that impairment of the PTHRP/PTHR1 signaling pathway in humans is associated with severe abnormalities in tooth and breast development. In addition to regulating human bone formation, this signaling pathway is also necessary for the normal development of the human breast and tooth.
Using the chick chorioallantoic membrane angiogenesis assay and mouse angiogenesis and tumor assays, Bakre et al. (2002) determined that PTHLH or a 10-amino acid peptide from its N terminus could inhibit endothelial cell migration in vitro and angiogenesis in vivo. Inhibition was mediated by activation of endothelial cell protein kinase A (PKA; see 176911), which in turn inhibited cell migration and angiogenesis by inhibiting the small GTPase Rac (see 602048). Conversely, inhibition of PKA reversed the antimigratory and antiangiogenesis properties of PTHLH.
Hsiao et al. (2002) described a case of B-cell lymphoma with hypercalcemia due to secretion of parathyroid hormone-related protein.
Using a Lewis lung carcinoma model of cancer cachexia, Kir et al. (2014) showed that PTHRP has an important role in wasting, through driving the expression of genes involved in thermogenesis in adipose tissues. Neutralization of Pthrp in tumor-bearing mice blocked adipose tissue browning and the loss of muscle mass and strength. Kir et al. (2014) concluded that PTHRP mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia.
Mizuhashi et al. (2018) demonstrated in a mouse model that skeletal stem cells are formed among Pthrp-positive chondrocytes within the resting zone of the postnatal growth plate. Pthrp-positive chondrocytes expressed a panel of markers for skeletal stem and progenitor cells, and uniquely possessed the properties of skeletal stem cells in cultured conditions. Cell lineage analysis revealed that Pthrp-positive chondrocytes in the resting zone continued to form columnar chondrocytes in the long term; these chondrocytes underwent hypertrophy, and became osteoblasts and marrow stromal cells beneath the growth plate. Transit-amplifying chondrocytes in the proliferating zone, which was concertedly maintained by a forward signal from undifferentiated cells (Pthrp) and a reverse signal from hypertrophic cells (Indian hedgehog, IHH; 600726), provided instructive cues to maintain the cell fates of Pthrp-positive chondrocytes in the resting zone. Mizuhashi et al. (2018) conclude that their findings unraveled a type of somatic stem cell that is initially unipotent and acquires multipotency at the postmitotic stage, underscoring the malleable nature of the skeletal cell lineage. They further concluded that this system provides a model in which functionally dedicated stem cells and their niches are specified postnatally, and maintained throughout tissue growth by a tight feedback regulation system.
In a family with brachydactyly type E (BDE; see 113300), Maass et al. (2010) identified a t(8;12)(q13;p11.2) translocation with breakpoints upstream of PTHLH on chromosome 12p11.2 and a disrupted KCNB2 (607738) on 8q13. Sequencing of the breakpoints identified a highly conserved activator protein-1 (AP1; see JUN, 165160) motif on 12p11.2, together with a C-ets-1 motif translocated from 8q13. AP1 and C-ets-1 bound in vitro and in vivo at the derivative chromosome 8 breakpoint, but were differently enriched between the wildtype and breakpoint allele. In chondrogenic cells from differentiated fibroblasts from BDE patients, PTHLH and its targets, ADAMTS7 (605009) and ADAMTS12 (606184), were downregulated along with impaired chondrogenic differentiation. In human and murine chondrocytes, the AP1 motif stimulated PTHLH promoter activity, whereas the derivative chromosome 8 breakpoint or C-ets-1 decreased PTHLH promoter activity.
In affected members of a 3-generation family segregating autosomal dominant brachydactyly type E (BDE2; 613382), short stature, and learning difficulties, Klopocki et al. (2010) performed array-based CGH and identified a 907.68-kb microdeletion on chromosome 12p that encompassed 6 known genes, of which only PTHLH was known to play a critical role in skeletal development. Klopocki et al. (2010) then analyzed the PTHLH gene in 4 unrelated families with BDE and short stature and identified heterozygous missense and nonsense mutations (168470.0001-168470.0004). None of the affected individuals in the 4 families had learning disabilities, suggesting that the deletion of the 5 genes distal to PTHLH most likely accounted for the additional phenotype.
Ihh, or Indian hedgehog (600726), induces the expression of a second signal, parathyroid hormone-related protein, in the periarticular perichondrium. Vortkamp et al. (1996) analyzed PTHRP -/- knockout mice and found that the PTHRP protein signals to its receptor in the prehypertrophic chondrocytes, thereby blocking hypertrophic differentiation. In vitro application of hedgehog or PTHRP protein to normal or PTHRP -/- limb explants demonstrated that PTHRP mediates the effects of Ihh through the formation of a negative feedback loop that modulates the rate of chondrocyte differentiation.
Lanske et al. (1996) investigated the functions of the PTH/PTHRP receptor (168468) by deletion of the murine gene by homologous recombination. Most receptor-negative mutant mice died in midgestation, a phenotype not observed in PTHRP -/- mice, perhaps because of the effects of maternal PTHRP. Mice that survived exhibited accelerated differentiation of chondrocytes in bone, and their bones, grown in explant culture, were resistant to the effects of PTHRP and Sonic hedgehog. Lanske et al. (1996) concluded that the PTH/PTHRP receptor mediates the effects of Indian hedgehog and PTHRP on chondrocyte differentiation.
Philbrick et al. (1998) found that whereas PTHRP knockout mice die at birth with a chondrodystrophic phenotype, replacement of PTHRP expression in the chondrocytes of these knockout mice using a procollagen II-driven transgene resulted in the correction of the lethal skeletal abnormalities and generated animals that were effectively PTHRP-null in all sites other than cartilage. These rescued PTHRP knockout mice survived to at least 6 months of age but were small in stature and displayed a number of developmental defects, including cranial chondrodystrophy and a failure of tooth eruption. Teeth appeared to develop normally but became trapped by the surrounding bone and underwent progressive impaction. Localization of PTHRP mRNA during normal tooth development by in situ hybridization showed increasing levels of expression in the enamel epithelium before the formation of the eruption pathway. The type 1 PTH/PTHRP receptor is expressed in both the adjacent dental mesenchyme and in alveolar bone. The replacement of PTHRP expression in the enamel epithelium with a keratin 14-driven transgene corrected the defect in bone resorption and restored the normal program of tooth eruption. PTHRP therefore represents an essential signal in the formation of the eruption pathway.
Lanske et al. (1999) compared the phenotypes of knockout mice for the PTHRP gene and the PTH/PTHRP receptor gene. One early phenotype is shared by both knockouts. Normally, the first chondrocytes to become hypertrophic are located in the centers of long bones; this polarity is greatly diminished in both knockouts. The receptor-deficient mice exhibited 2 unique phenotypes not shared by the PTHRP mice. During intramembranous bone formation in the shafts of long bones, only the receptor-deficient bones exhibited a striking increase in osteoblast number and matrix accumulation; furthermore, the receptor-deficient mice showed a dramatic decrease in trabecular bone formation in the primary spongiosa and a delay in vascular invasion of the early cartilage model. In the double-homozygous knockout mice, the delay in vascular invasion did not occur. Thus, PTHRP must slow vascular invasion by a mechanism independent of the PTH/PTHRP receptor.
Miao et al. (2002) compared the skeletal development of newborn mice lacking either Pth, Pthlh, or both peptides. Pth-deficient mice were dysmorphic but viable. They demonstrated diminished cartilage matrix mineralization, decreased neovascularization with reduced expression of angiopoietin-1 (601667), and reduced metaphyseal osteoblasts and trabecular bone. Mice lacking Pthlh died at birth with dyschondroplasia. Compound mutants displayed the combined cartilaginous and osseous defects of both single mutants, indicating that both hormones are required to achieve normal fetal skeletal morphogenesis, and they demonstrated an essential function of Pth at the cartilage-bone interface.
In the mouse, the Pthlh gene is a candidate for a skin carcinogenesis susceptibility locus mapping to distal mouse chromosome 6 (Manenti et al., 2000). Dragani (2003) noted that Pthlh shows a thr166-to-pro amino acid polymorphism. The pro and thr alleles are linked with high and low genetic susceptibility, respectively, to 2-stage skin carcinogenesis of outbred susceptible and resistant mice.
Although the symbol PTHR was used for parathyroid hormone-like hormone, the approved symbol is PTHLH. The symbol PTHR has also been used for the parathyroid hormone receptor, now designated PTHR1 (168468).
Humoral hypercalcemia of malignancy (HHM) is a common complication of certain cancers, especially squamous cell carcinoma of the lung, in which it contributes substantially to morbidity and mortality. The syndrome of humoral hypercalcemia of cancer was first described by Albright (1941). When a patient's hypercalcemia and hypophosphatemia resolved after the radiation of a single bone metastasis from a renal carcinoma, Albright proposed that the tumor was secreting parathyroid hormone or a peptide with similar actions. Studies of the mechanisms that underlie humoral hypercalcemia of cancer led to the description of 3 classes of peptides: growth factor-like peptides, parathyroid-like peptides, and bone-resorbing factors distinct from either of the other two. As outlined by Broadus et al. (1988), delineation of the parathyroid hormone-like protein has gone through 4 phases: clinical and descriptive studies; in vitro studies; protein purification; and molecular studies.
In a 41-year-old woman with brachydactyly type E2 (613382) involving metacarpals III-V and the middle phalanges of II and IV and short stature, Klopocki et al. (2010) identified heterozygosity for a 179T-C transition in exon 3 of the PTHLH gene, resulting in a leu60-to-pro (L60P) substitution. Overexpression of murine wildtype and mutant Pthlh in chicken limb micromass culture using a retroviral system showed significantly weaker suppression of alkaline phosphatase with the mutant than wildtype, indicating a loss of function in the mutant. The mutation was not detected in 200 controls.
In a 9-year-old girl with brachydactyly type E2 (613382) and normal stature, Klopocki et al. (2010) identified heterozygosity for a 131T-C transition in exon 3 of the PTHLH gene, resulting in a leu44-to-pro (L44P) substitution. Radiography in the patient showed cone-shaped epiphyses of several phalanges and premature fusion of epiphyses, and problems with tooth eruption of primary as well as secondary teeth were reported. The mutation was not detected in 200 controls.
In a 14-year-old girl from a 3-generation family with brachydactyly type E2 (613382) and short stature, Klopocki et al. (2010) identified heterozygosity for a 532A-G transition in exon 4 of the PTHLH gene, resulting in a ter178-to-trp (X178W) substitution and extending the coding region. The patient had shortened metacarpals III and V, abnormal metacarpal epiphyses prematurely fused to the metaphyses, and hypoplastic nails of the first fingers. Her mother had short fifth metacarpals and the maternal grandfather was reported to have short stature and brachydactyly, but material for testing was not available. The mutation was not detected in 200 controls.
In the proband from a family with brachydactyly type E2 (613382), short stature, and oligodontia, Klopocki et al. (2010) identified heterozygosity for a T-C transition in exon 3 of the PTHLH gene, resulting in a lys120-to-ter (K120X) substitution and truncation of the protein within the nuclear localization signal. The mutation was not detected in 200 controls. The proband and her sister had 9 and 26 missing teeth, respectively. Their mother was reported to have been of normal stature with normal hands and feet, but information was not available on their father. The sister's son was also affected.
Albright, F. Case records of the Massachusetts General Hospital (case 27461). New Eng. J. Med. 225: 789-791, 1941.
Bakre, M. M., Zhu, Y., Yin, H., Burton, D. W., Terkeltaub, R., Deftos, L. J., Varner, J. A. Parathyroid hormone-related peptide is a naturally occurring, protein kinase A-dependent angiogenesis inhibitor. Nature Med. 8: 995-1003, 2002. [PubMed: 12185361] [Full Text: https://doi.org/10.1038/nm753]
Broadus, A. E., Mangin, M., Ikeda, K., Insogna, K. L., Weir, E. C., Burtis, W. J., Stewart, A. F. Humoral hypercalcemia of cancer: identification of a novel parathyroid hormone-like peptide. New Eng. J. Med. 319: 556-563, 1988. [PubMed: 3043221] [Full Text: https://doi.org/10.1056/NEJM198809013190906]
Dragani, T. A. 10 Years of mouse cancer modifier loci: human relevance. Cancer Res. 63: 3011-3018, 2003. [PubMed: 12810618]
Hammonds, R. G., Jr., McKay, P., Winslow, G. A., Diefenbach-Jagger, H., Grill, V., Glatz, J., Rodda, C. P., Moseley, J. M., Wood, W. I., Martin, T. J. Purification and characterization of recombinant human parathyroid hormone-related protein. J. Biol. Chem. 264: 14806-14811, 1989. [PubMed: 2549037]
Hendy, G. N., Sakaguchi, A. Y., Lalley, P. A., Martinez, L., Yasuda, T., Banville, D., Goltzman, D. Gene for parathyroid hormone-like peptide is on mouse chromosome 6. (Abstract) Cytogenet. Cell Genet. 51: 1003 only, 1989.
Hendy, G. N., Sakaguchi, A. Y., Lalley, P. A., Martinez, L., Yasuda, T., Banville, D., Goltzman, D. Gene for parathyroid hormone-like peptide is on mouse chromosome 6. Cytogenet. Cell Genet. 53: 80-82, 1990. [PubMed: 1973379] [Full Text: https://doi.org/10.1159/000132899]
Henry, J. G., Mitnick, M., Dann, P. R., Stewart, A. F. Parathyroid hormone-related protein-(1-36) is biologically active when administered subcutaneously to humans. J. Clin. Endocr. Metab. 82: 900-906, 1997. [PubMed: 9062504] [Full Text: https://doi.org/10.1210/jcem.82.3.3811]
Holick, M. F., Ray, S., Chen, T. C., Tian, X., Persons, K. S. A parathyroid hormone antagonist stimulates epidermal proliferation and hair growth in mice. Proc. Nat. Acad. Sci. 91: 8014-8016, 1994. [PubMed: 8058749] [Full Text: https://doi.org/10.1073/pnas.91.17.8014]
Hsiao, L.-T., Chiou, T.-J., Yu, I.-T., Chen, P.-M. Superior vena cava syndrome and hypercalcaemia in a patient with a primary mediastinal B-cell lymphoma secreting parathyroid hormone-related protein. Brit. J. Haemat. 119: 1 only, 2002. [PubMed: 12358896] [Full Text: https://doi.org/10.1046/j.1365-2141.2002.03720.x]
Karaplis, A. C., Luz, A., Glowacki, J., Bronson, R. T., Tybulewicz, V. L. J., Kronenberg, H. M., Mulligan, R. C. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev. 8: 277-289, 1994. [PubMed: 8314082] [Full Text: https://doi.org/10.1101/gad.8.3.277]
Kir, S., White, J. P., Kleiner, S., Kazak, L., Cohen, P., Baracos, V. E., Spiegelman, B. M. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 513: 100-104, 2014. [PubMed: 25043053] [Full Text: https://doi.org/10.1038/nature13528]
Klopocki, E., Hennig, B. P., Dathe, K., Koll, R., de Ravel, T., Baten, E., Blom, E., Gillerot, Y., Weigel, J. F. W., Kruger, G., Hiort, O., Seemann, P., Mundlos, S. Deletion and point mutations of PTHLH cause brachydactyly type E. Am. J. Hum. Genet. 86: 434-439, 2010. [PubMed: 20170896] [Full Text: https://doi.org/10.1016/j.ajhg.2010.01.023]
Lanske, B., Amling, M., Neff, L., Guiducci, J., Baron, R., Kronenberg, H. M. Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development. J. Clin. Invest. 104: 399-407, 1999. [PubMed: 10449432] [Full Text: https://doi.org/10.1172/JCI6629]
Lanske, B., Karaplis, A. C., Lee, K., Luz, A., Vortkamp, A., Pirro, A., Karperien, M., Defize, L. H. K., Ho, C., Mulligan, R. C., Abou-Samra, A.-B., Juppner, H., Segre, G. V., Kronenberg, H. M. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273: 663-666, 1996. [PubMed: 8662561] [Full Text: https://doi.org/10.1126/science.273.5275.663]
Maass, P. G., Wirth, J., Aydin, A., Rump, A., Stricker, S., Tinschert, S., Otero, M., Tsuchimochi, K., Goldring, M. B., Luft, F. C., Bahring, S. A cis-regulatory site downregulates PTHLH in translocation t(8;12)(q13;p11.2) and leads to brachydactyly type E. Hum. Molec. Genet. 19: 848-860, 2010. [PubMed: 20015959] [Full Text: https://doi.org/10.1093/hmg/ddp553]
Manenti, G., Peissel, B., Gariboldi, M., Falvella, F. S., Zaffaroni, D., Allaria, B., Pazzaglia, S., Rebessi, S., Covelli, V., Saran, A., Dragani, T. A. A cancer modifier role for parathyroid hormone-related protein. Oncogene 19: 5324-5328, 2000. [PubMed: 11103933] [Full Text: https://doi.org/10.1038/sj.onc.1203916]
Mangin, M., Ikeda, K., Dreyer, B. E., Broadus, A. E. Isolation and characterization of the human parathyroid hormone-like peptide gene. Proc. Nat. Acad. Sci. 86: 2408-2412, 1989. [PubMed: 2928340] [Full Text: https://doi.org/10.1073/pnas.86.7.2408]
Mangin, M., Webb, A. C., Dreyer, B. E., Posillico, J. T., Ikeda, K., Weir, E. C., Stewart, A. F., Bander, N. H., Milstone, L., Barton, D. E., Francke, U., Broadus, A. E. Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy. Proc. Nat. Acad. Sci. 85: 597-601, 1988. [PubMed: 2829195] [Full Text: https://doi.org/10.1073/pnas.85.2.597]
Miao, D., He, B., Karaplis, A. C., Goltzman, D. Parathyroid hormone is essential for normal fetal bone formation. J. Clin. Invest. 109: 1173-1182, 2002. [PubMed: 11994406] [Full Text: https://doi.org/10.1172/JCI14817]
Mizuhashi, K., Ono, W., Matsushita, Y., Sakagami, N., Takahashi, A., Saunders, T. L., Nagasawa, T., Kronenberg, H. M., Ono, N. Resting zone of the growth plate houses a unique class of skeletal stem cells. Nature 563: 254-258, 2018. [PubMed: 30401834] [Full Text: https://doi.org/10.1038/s41586-018-0662-5]
Moseley, J. M., Kubota, M., Diefenbach-Jagger, H., Wettenhall, R. E. H., Kemp, B. E., Suva, L. J., Rodda, C. P., Ebeling, P. R., Hudson, P. J., Zajac, J. D., Martin, T. J. Parathyroid hormone-related protein purified from a human lung cancer cell line. Proc. Nat. Acad. Sci. 84: 5048-5052, 1987. [PubMed: 2885845] [Full Text: https://doi.org/10.1073/pnas.84.14.5048]
Philbrick, W. M., Dreyer, B. E., Nakchbandi, I. A., Karaplis, A. C. Parathyroid hormone-related protein is required for tooth eruption. Proc. Nat. Acad. Sci. 95: 11846-11851, 1998. [PubMed: 9751753] [Full Text: https://doi.org/10.1073/pnas.95.20.11846]
Strewler, G. J. The physiology of parathyroid hormone-related protein. New Eng. J. Med. 342: 177-185, 2000. [PubMed: 10639544] [Full Text: https://doi.org/10.1056/NEJM200001203420306]
Suva, L. J., Winslow, G. A., Wettenhall, R. E. H., Hammonds, R. G., Moseley, J. M., Diefenbach-Jagger, H., Rodda, C. P., Kemp, B. E., Rodriguez, H., Chen, E. Y., Hudson, P. J., Martin, T. J., Wood, W. I. A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science 237: 893-896, 1987. [PubMed: 3616618] [Full Text: https://doi.org/10.1126/science.3616618]
Vortkamp, A., Lee, K., Lanske, B., Segre, G. V., Kronenberg, H. M., Tabin, C. J. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273: 613-622, 1996. [PubMed: 8662546] [Full Text: https://doi.org/10.1126/science.273.5275.613]
Wysolmerski, J. J., Cormier, S., Philbrick, W. M., Dann, P., Zhang, J.-P., Roume, J., Delezoide, A.-L., Silve, C. Absence of functional type 1 parathyroid hormone (PTH)/PTH-related protein receptors in humans is associated with abnormal breast development and tooth impaction. J. Clin. Endocr. Metab. 86: 1788-1794, 2001. [PubMed: 11297619] [Full Text: https://doi.org/10.1210/jcem.86.4.7404]
Wysolmerski, J. J., Philbrick, W. M., Dunbar, M. E., Lanske, B., Kronenberg, H., Broadus, A. E. Rescue of the parathyroid hormone-related protein knockout mouse demonstrates that parathyroid hormone-related protein is essential for mammary gland development. Development 125: 1285-1294, 1998. [PubMed: 9477327] [Full Text: https://doi.org/10.1242/dev.125.7.1285]
Yasuda, T., Banville, D., Hendy, G. N., Goltzman, D. Characterization of the human parathyroid hormone-like peptide gene: functional and evolutionary aspects. J. Biol. Chem. 264: 7720-7725, 1989. [PubMed: 2708388]