Parathyroid Hormone-related Protein (PTHrP) is a protein hormone found throughout the body, not solely within the parathyroid glands. This protein is a member of the parathyroid hormone family and is secreted by various cell types, including mesenchymal stem cells. PTHrP’s widespread presence highlights its importance across numerous biological processes. It functions as an endocrine, autocrine, paracrine, and intracrine hormone, indicating its diverse modes of action.
Physiological Roles of PTHrP
PTHrP plays a role in maintaining the body’s calcium balance, particularly through local regulation. It contributes to calcium homeostasis by influencing processes like bone resorption and calcium reabsorption in the kidneys.
The protein is also involved in bone development and remodeling, especially during fetal growth. It helps regulate endochondral bone development by maintaining the constant width of the endochondral growth plate, which is a temporary cartilage structure where most bones grow during childhood. PTHrP produced by osteoblasts, cells responsible for bone formation, regulates this process.
PTHrP also influences the relaxation of smooth muscles. It affects the smooth muscle cells in blood vessels, contributing to vascular tone, and plays a role in the uterus, impacting its relaxation. This broad impact on smooth muscle function highlights its diverse physiological contributions.
Another function of PTHrP is its involvement in mammary gland development and lactation. It regulates the epithelial-mesenchymal interactions necessary for the formation of breast tissue. This protein is also involved in milk production, demonstrating its direct role in mammary gland processes.
Distinguishing PTHrP from Parathyroid Hormone
PTHrP and PTH share similarities, which allows them to bind to the same receptor, the PTHR1 receptor. This allows PTHrP to mimic some of PTH’s actions, such as increasing bone resorption and promoting calcium reabsorption in the distal renal tubules.
Despite these overlapping effects, PTHrP and PTH are distinct proteins produced by different tissues and regulated independently. PTH is primarily produced by the parathyroid glands and is the main systemic regulator of blood calcium levels. In contrast, PTHrP is expressed in a wide variety of tissues throughout the body and acts locally, influencing cellular processes.
Their physiological roles also differ; PTH’s main function is to maintain systemic calcium and phosphate homeostasis, while PTHrP has more localized and developmental roles. For instance, PTHrP is involved in fetal development, bone growth, and mammary gland development, functions not primarily attributed to PTH. Both proteins have a common evolutionary origin, accounting for their structural and functional similarities.
PTHrP in Disease States
PTHrP is implicated in Humoral Hypercalcemia of Malignancy (HCM), a common paraneoplastic syndrome. In HCM, certain cancers, such as breast, lung, head, and neck cancers, as well as some leukemias and lymphomas, produce and secrete PTHrP. This excess PTHrP then acts on bone and kidney cells, leading to elevated blood calcium levels, a condition called hypercalcemia.
The symptoms of hypercalcemia include fatigue, increased thirst and urination, nausea, constipation, and in severe cases, confusion or heart rhythm abnormalities. PTHrP-mediated hypercalcemia is a clinical concern, sometimes being the initial indicator of an underlying malignancy. The protein stimulates osteoclastic bone resorption, promoting the breakdown of bone to release calcium into the bloodstream. It also enhances calcium reabsorption in the kidneys, further contributing to the elevated calcium levels.
Beyond HCM, PTHrP plays a role in other disease contexts, though less common or still under investigation. Its involvement has been explored in certain bone metastases, where cancer cells spread to the bone. Research is exploring potential applications of PTHrP administration as a treatment for conditions like osteoporosis, where it has anabolic effects on bone, and in certain cancers or diabetes. The complex roles of PTHrP in various pathological conditions continue to be an area of active scientific inquiry.