Parathyroid hormone-related protein (PTHrP) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

aceous

hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...

and a member of the

parathyroid hormone family The parathyroid hormone family is a family of structurally and functionally related proteins. Parathyroid hormone (PTH) is a polypeptidic hormone primarily involved in calcium metabolism. The parathyroid hormone-related protein (PTH-rP) is a re ...

secreted by

mesenchymal stem cell Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells or medicinal signaling cells, are multipotent stromal cells that can Cellular differentiation, differentiate into a variety of cell types, including osteoblasts (bone cells), ...

s. It is occasionally secreted by

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

cells (for example,

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

, certain types of

lung cancer Lung cancer, also known as lung carcinoma, is a malignant tumor that begins in the lung. Lung cancer is caused by genetic damage to the DNA of cells in the airways, often caused by cigarette smoking or inhaling damaging chemicals. Damaged ...

including squamous-cell lung carcinoma). However, it also has normal functions in

bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...

teeth A tooth (: teeth) is a hard, calcified structure found in the jaws (or mouths) of many vertebrates and used to break down food. Some animals, particularly carnivores and omnivores, also use teeth to help with capturing or wounding prey, tear ...

vascular tissue Vascular tissue is a complex transporting tissue, formed of more than one cell type, found in vascular plants. The primary components of vascular tissue are the xylem and phloem. These two tissues transport fluid and nutrients internally. T ...

s and other tissues.

Function

PTHrP acts as an

endocrine The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...

autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with ...

paracrine In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication (biology), cellular communication in which a Cell (biology), cell produces a signal to induce changes in nearby cells, altering the behaviour of ...

, and

intracrine Intracrine signaling is a mode of hormone and growth factor action in which signaling molecules exert their effects within the same cell that produces them, without being secreted into the extracellular environment. The term intracrine was origin ...

hormone. It regulates endochondral bone development by maintaining the endochondral growth plate at a constant width. It also regulates epithelial–mesenchymal interactions during the formation of the mammary glands. PTHrP plays a major role in regulating calcium homeostasis in vertebrates, including sea bream, chick, and mammals. In 2005, Australian pathologist and researcher

Thomas John Martin Thomas may refer to: People * List of people with given name Thomas * Thomas (name) * Thomas (surname) * Saint Thomas (disambiguation) * Thomas Aquinas (1225–1274) Italian Dominican friar, philosopher, and Doctor of the Church * Thomas the A ...

found that PTHrP produced by

osteoblast Osteoblasts (from the Greek combining forms for " bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts fu ...

s is a physiological regulator of

bone formation Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in th ...

. Martin and Miao ''et al.'' demonstrated that osteoblast-specific

ablation Ablation ( – removal) is the removal or destruction of something from an object by vaporization, chipping, erosion, erosive processes, or by other means. Examples of ablative materials are described below, including spacecraft material for as ...

of PTHrP in mice results in osteoporosis and impaired bone formation both in vivo and ex vivo, which reiterates the

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...

of mice with

haploinsufficiency Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...

of PTHrP. By these findings, they demonstrated that PTHrP plays a central role in physiological regulation of bone formation by promoting recruitment and survival of osteoblasts. It may also play a role in physiological regulation of

bone resorption Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood. The osteoclasts are multi-nuclea ...

by enhancing

osteoclast An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and bone remodeling, remodeling of bones of the vertebrate, vertebral skeleton. The osteoclast disassembles and digests th ...

formation.

Tooth eruption

PTHrP is critical in intraosseous phase of tooth eruption where it acts as a signalling molecule to stimulate local bone resorption. Without PTHrP, the bony crypt surrounding the tooth follicle will not resorb, and therefore the tooth will not erupt. In the context of tooth eruption, PTHrP is secreted by the cells of the reduced enamel epithelium.

Mammary glands

It aids in normal

mammary gland development Breast development, also known as mammogenesis, is a complex biological process in primates that takes place throughout a female's life. It occurs across several phases, including prenatal development, puberty, and pregnancy. At menopause, breas ...

. It is necessary for maintenance of the mammary bud cells. Loss of PTHrP or its receptor causes the mammary bud cells to change back into

epidermal cell The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermal layer provides a barrier to infection from environmental pathogens and regulates the amount of water relea ...

s. In

lactation Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The process ...

, it may regulate the mobilization and transfer of

calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...

to the milk in conjunction with the calcium sensing receptors, as well as

placenta The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...

l transfer of calcium.

Humoral hypercalcemia of malignancy

PTHrP is related in function to parathyroid hormone(PTH). When a

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

secretes PTHrP, this can lead to

hypercalcemia Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range for total calcium is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L def ...

. As this is sometimes the first sign of the

malignancy Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not ...

, hypercalcemia caused by PTHrP is considered a paraneoplastic phenomenon. PTHrP is responsible for most cases of humoral hypercalcemia of malignancy. PTHrP shares the same

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

end as parathyroid hormone and therefore it can bind to the same receptor, the Type I PTH receptor ( PTHR1). PTHrP can simulate most of the actions of PTH including increases in bone resorption and distal tubular calcium reabsorption, and inhibition of proximal tubular phosphate transport. PTHrP lacks the normal feedback inhibition as PTH. However, PTHrP has a less sustained action than PTH on PTHR1 activation, which may explain at least in part its reduced ability to stimulate 1,25-dihydroxyvitamin D (1,25(OH)₂ vitamin D) production and indirectly intestinal calcium absorption through an action to increase circulating levels of 1,25(OH)₂ vitamin D.

Growth Plate

PTHrP is found in the proliferative zone of the growth plate. It is one of the main proteins that regulates mesenchymal stem cell activity. Current research suggests that PTHrP promotes the proliferation of early-phase chondrocytes and inhibits their differentiation into hypertropic chondrocytes. It is involved in a

negative feedback Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused ...

loop with Indian Hedgehog (Ihh).

Genetics

Four

alternatively spliced Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

transcript variants encoding two distinct

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

s have been observed. There is also evidence for alternative translation initiation from non-AUG (CUG and GUG) start sites, in-frame and downstream of the initiator AUG codon, to give rise to nuclear forms of this hormone.

Discovery

The protein was first isolated in 1987 by Thomas J. Martin's team at the

University of Melbourne The University of Melbourne (colloquially known as Melbourne University) is a public university, public research university located in Melbourne, Australia. Founded in 1853, it is Australia's second oldest university and the oldest in the state ...

. Miao ''et al''. showed that disruption of the ''PTHrP'' gene in mice caused a lethal phenotype and distinct bone abnormalities, suggesting that PTHrP has a physiological function.

Interactions

Parathyroid hormone-related protein has been shown to interact with

KPNB1 Importin subunit beta-1 is a protein that in humans is encoded by the ''KPNB1'' gene. Function Nucleocytoplasmic transport, a signal- and energy-dependent process, takes place through nuclear pore complexes embedded in the nuclear envelope. T ...

and Arrestin beta 1.