Anti-PTHRP (aa 1-34) monoclonal antibody, clone 34-68-248-2

Parathyroid hormone-related protein (PTHRP) is a protein purified by researchers from human tumor tissue. By cloning its cDNA sequence, it was found that 8 of the first 13 residues of this substance are identical to those in PTH. Interestingly, the study found that the biological activities of the first 34 amino acids of this substance include the known biological activities of PTH, including increasing blood calcium and lowering blood phosphorus. PTHRP and PTH have similar intron and exon boundaries, but the gene structure of PTHRP is more complex than that of PTH, and the first 111 positions of the PTHRP amino acid sequence in humans, rats, mice, chickens and dogs Conservative. PTHRP has many paracrine effects in physiological homeostasis, including the development of keratinocytes, hair follicles, cartilage, vascular smooth muscle, bone, breast and other tissues. At the same time, new research shows that PTHRP also plays an endocrine regulatory role in tumor-related hypercalcemia, lactation breasts, and fetal growth and development.

Figure 1. Parathyroid hormone-related protein (PTHRP) evolution. (Source: Torday JS. 2015)

Mice homozygous for unintentional mutations in parathyroid-related protein are lethal. During endochondral bone formation, chondrocytes serve as templates for future bone growth. Chondrocytes proliferate in a specific manner and secrete the corresponding extracellular matrix. When the proliferation phase is over, chondrocytes will enter a terminal differentiation state. First, chondrocytes become hypertrophic and initiate the matrix synthesis program, mineralize the extracellular matrix they secrete, and finally undergo apoptosis and programmed cell death. The already mineralized bone prototype will be immediately invaded by osteocytes, which then absorb the cartilage scaffold to achieve bone replacement. In mice that have undergone homologous recombination, in the absence of parathyroid hormone-related protein, chondrocytes cannot proliferate normally, resulting in shortened bones. By targeting cartilage-specific type II collagen as a promoter to overexpress PTHTP protein in mouse chondrocytes, mice that successfully overexpressed parathyroid hormone-related protein in cartilage had severely delayed chondrocyte maturation, and apoptosis are suspended, and islands of chondrocytes persist within mature bone. Given that PTHRP is extensively involved in normal chondrocyte and bone biology, it is not surprising that changes in PTHRP function are associated with bone diseases. The most obvious case is humoral hypercalcemia of malignancy (HHM), in which PTHRP protein in circulating blood interacts with PTHR1 receptors in bone to induce extensive bone resorption and produce hypercalcemia. Loss-of-function mutations in the PTHR1 gene cause chondrodysplasia, which is associated with bone abnormalities that mimic PTHRP knockout mice and lead to fetal death. Not only in experimental animals but also in the clinic, loss-of-function mutations in PTHLH (the gene encoding the PTHRP protein) have recently been shown to cause brachydactyly E, a syndrome that includes short stature, shortened palms and metatarsals, and learning disabilities.

In addition, studies have found that PTHRP signaling is necessary for mammary gland formation. Fetuses with achondroplasia are also accompanied by congenital loss of breast tissue, which confirms that PTHRP signaling is also required for human breast development. During the formation of the mammary gland, the epithelial cells will appear bud-like invaginations, which will develop into the fat matrix in the mammary gland duct system and help the development of branch ducts. The life activities in this process are regulated by themesenchymal cells in the surrounding matrix. During the formation of mouse and human fetuses, epithelial cells in the mammary gland bud can produce PTHRP, which can interact with PTHR1 expressed on the outer membrane of surrounding mesenchymal cells. This interaction is essential for the correct differentiation of mesenchymal cells, and this process also triggers the growth of epithelial ducts. In addition to its role in fetal mammary gland development, PTHRP also plays an important role in the placental transport of calcium ions and other nutrients during pregnancy in humans and rodents. Studies have found that the placenta can produce PTHRP, and its secretion is regulated by the CaSR pathway. Studies on PTHRP knockout mice have shown that PTHRP promotes calcium transport from mother to fetus and helps maintain normal fetal calcium concentrations. In addition, PTHRP is also involved in muscle stretching and expansion. For example, PTHRP can be released by various smooth muscles in response to mechanical stretch, and binding of PTHRP to receptors can cause smooth muscle dilation in response to vasoconstrictors such as angiotensin II. The response of parathyroid hormone-related proteins in smooth muscle tissue to external stimuli is based on the electrical signals generated by the local relaxation smooth muscle in the stretch short loop feedback system. Similar pathways and mechanisms can also occur in uterine smooth muscle tissue during delivery. PTHRP can regulate smooth muscle to send expansion signals. It has similar regulatory effects on bladder smooth muscle and arterial hypertension. In cardiac tissue, PTHRP protein can be released by atrial and ventricular myocytes and has a positive frequency effect. More interestingly, studies have found that pancreatic islets express PTHRP under normal physiological activities, and PTHRP expression exceeding normal levels can also be detected in islet cell adenomas and carcinomas. At the same time, pancreatic islet β cells also contain PTHRP receptors, which also illustrates from the side that PTHRP can play a normal regulatory or developmental role in pancreatic islets.

Parathyroid Hormone-like Protein
PTH-like Protein
PTH-related Peptide
Parathyroid Hormone-related Peptide