Background Information on the Parathyroid Hormone (PTH)
The parathyroid hormone, typically referred to as PTH, is a hormone synthesized and released by the parathyroid glands, which are tiny endocrine glands located in the neck. The integral discovery of PTH is traced back to the 1920s and 1930s, when Dr. James B. Collip became the first to isolate a hormone from the parathyroid glands. PTH is crucial for bone metabolism and calcium-ion homeostasis.
The parathyroid hormone gene (PTH) is found on chromosome 11p15, specifically at gene locus 11p15.3. This gene encodes a preproprotein that is subsequently cleaved to generate a signal peptide, which is removed to yield the proprotein, then subsequently processed into the functional hormone. PTH protein is distinctive, with a single-chain structure comprised of 84 amino acids.
Parathyroid Hormone Function
PTH primarily regulates serum calcium levels in the body. It enhances calcium concentration in the blood by stimulating bone resorption (a process involving the breakdown of bone to release calcium) by osteoclasts; promoting calcium reabsorption by renal tubules; and indirectly increasing intestinal calcium absorption through vitamin D activation. It counteracts the action of calcitonin, a hormone that lowers calcium levels in the blood.
Parathyroid Hormone-Related Signaling Pathways
PTH chiefly exerts its actions through parathyroid hormone 1 receptor (PTH1R), a G protein-coupled receptor expressed predominantly in bone and kidney cells. Here, it sets two main pathways into motion: the Protein Kinase A (PKA) pathway and the Protein Kinase C (PKC) pathway.
The PKA pathway is conventionally activated by PTH-induced cyclic adenosine monophosphate (cAMP) production, triggering a myriad of downstream effects that ultimately stimulate osteoblast-driven bone formation and calcium reabsorption in kidneys. Conversely, the PKC pathway promotes rapid intra-cellular calcium release, leading to the calcemic effects of PTH.
Parathyroid Hormone-Related Diseases and the Role of Interferon beta-1a
Primary hyperparathyroidism, characterized by excess PTH production, and hypoparathyroidism, marked by insufficient PTH production, are the main disorders directly related to PTH. These conditions result in abnormal calcium levels, which can harm various physiological systems.
Interferon beta-1a is commonly used in the treatment of multiple sclerosis, but it can lead to changes in calcium metabolism and PTH levels in some patients. Although not fully understood, researchers believe it may down-regulate PTH production or interfere with calcium regulatory mechanisms.
The Application of Parathyroid Hormone in Medicine
Clinically, PTH is a significant diagnostic and therapeutic tool. In diagnostics, PTH assays help identify and manage hyperparathyroidism and other calcium disorders. Therapeutically, human recombinant PTH1-34 (Teriparatide) has been approved for treating osteoporosis, enhancing new bone formation.
List of Drug Candidates Related to Parathyroid Hormone
Several drug candidates related to PTH are in different stages of development. These include:
Abaloparatide: A peptide related to PTH, used for osteoporosis treatment.
Natpara: A bio-engineered replica of human PTH used as a replacement therapy for hypoparathyroidism.
FAHR-201: A new conjugate of PTH(1-34) peptide and hyaluronic acid in preclinical trials for osteoporosis.
TransCon PTH: An investigational long-acting prodrug of PTH in clinical development for hypoparathyroidism.
