From the culture medium of a human lung cancer cell line, Moseley et al. (1987) purified a protein with biologic activities similar to parathyroid hormone. 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.
NCBI Summary:
Parathyroid-related protein, signaling through its receptor, PTHR1 (MIM 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.[supplied by OMIM]
General function
Ligand, Hormone
Comment
Cellular localization
Secreted
Comment
Ovarian function
Oogenesis, Early embryo development
Comment
The Roles of Parathyroid Hormone-Like Hormone during Mouse Preimplantation Embryonic Development. Guo L et al. Parathyroid hormone-like hormone (PTHLH) was first identified as a parathyroid hormone (PTH)-like factor responsible for humoral hypercalcemia in malignancies in the 1980s. Previous studies demonstrated that PTHLH is expressed in multiple tissues and is an important regulator of cellular and organ growth, development, migration, differentiation, and survival. However, there is a lack of data on the expression and function of PTHLH during preimplantation embryonic development. In this study, we investigated the expression characteristics and functions of PTHLH during mouse preimplantation embryonic development. The results show that Pthlh is expressed in mouse oocytes and preimplantation embryos at all developmental stages, with the highest expression at the MII stage of the oocytes and the lowest expression at the blastocyst stage of the preimplantation embryos. The siRNA-mediated depletion of Pthlh at the MII stage oocytes or the 1-cell stage embryos significantly decreased the blastocyst formation rate, while this effect could be corrected by culturing the Pthlh depleted embryos in the medium containing PTHLH protein. Moreover, expression of the pluripotency-related genes Nanog and Pou5f1 was significantly reduced in Pthlh-depleted embryos at the morula stage. Additionally, histone acetylation patterns were altered by Pthlh depletion. These results suggest that PTHLH plays important roles during mouse preimplantation embryonic development.
Small cell carcinomas (SCC) are the most common ovarian tumors associated with hypercalcemia. Parathyroid hormone-related protein (PTHrp) is the most frequent cause of hypercalcemia of malignancy. Matias-Guiu et al found that PTHrp plays a role in the development of hypercalcemia in patients with SCC of the ovary Matias-Guiu et al. (1994). Garmey et al. (2000) found that PTH-rp (1 muM) stimulated intracellular free calcium ion concentrations ([Ca(2+)](i)) in single porcine theca cells. The [Ca(2+)](i) elevation was characterized by a slow and prolonged rise. After PTH-rp stimulation, theca cells maintained responsiveness to hormone stimulation by LH, which elicited a typical theca cell [Ca(2+)](i) response.
Expression regulated by
Growth Factors/ cytokines
Comment
Transforming growth factor (TGF)-beta1 (100 ng/ml) increased PTH-rp concentrations (assayed by
two-site immunoradiometric assay of culture media) as well as corresponding PTH-rp mRNA accumulation (assessed by
RT-PCR) in a time-dependent manner, with maximal responses of 3- to 5-fold at 96 h. TGF-beta1 dose-response studies
revealed an ED(50) of 0.24-0.38 ng/ml with a maximal effect at 30 ng/ml. Other growth factors and hormones, including
insulin, insulin-like growth factor (type I), epidermal growth factor, FSH, estradiol, and interleukin-1, failed to alter PTH-rp
secretion Garmey et al. (2000).
Ovarian localization
Oocyte, Granulosa, Theca, Luteal cells
Comment
Asa et al. (1990) found PTHrP immunostaining in ovarian granulosa and thecal cells. Garmey et al. (2000) found that PTH-rp gene is expressed at high levels in porcine corpus luteum but is undetectable in granulosa and theca cells isolated from small and medium-sized antral follicles. Watson PH, et al 2001 reported the expression of PTHrP and PTHR (PTH/PTHrP-r) mRNAs and
polypeptides in bovine ovary and stimulation of bovine
blastocyst development in vitro following PTHrP treatment
during oocyte maturation.
mRNAs encoding PTHrP and PTHR
were detected by in situ hybridization methods in oocytes, and granulosa cells
in all follicles from primordial to large antral. PTHrP and PTHR polypeptides
displayed distinct distribution patterns with PTHrP polypeptides primarily
confined to oocytes from primordial to large antral follicles. PTHrP polypeptides were detectable but at a reduced level in ovarian stroma and in
granulosa and thecal layers. PTHR polypeptides were detected in oocytes of all follicular stages but were predominantly found in ovarian stroma, granulosa
and theca follicular layers. Supplementation of serum-free cSOFMaa oocyte
maturation medium with PTHrP (1-141) resulted in a concentration-dependent
increase in development to the blastocyst stage in vitro. The results suggest
that granulosa cells may be a primary site of PTHrP production and release.
Oocytes from all follicular stages stained strongly for PTHrP polypeptides and
PTHrP enhanced development to the blastocyst stage in vitro.
Follicle stages
Secondary, Antral, Preovulatory
Comment
Gutmann et al. (1993) reported that human granulosa-luteal cells secrete parathyroid hormone-related protein in vivo and in vitro.
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: embryonic lethal Comment:Philbrick et al. (1998) reported that parathyroid hormone (PTH)-related protein (PTHrP)-knockout mice die at birth with a chondrodystrophic phenotype characterized by premature chondrocyte differentiation and accelerated bone formation.