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A 47-year-old woman with a history of excessive blood calcium levels was diagnosed with parathyroid gland cancer that had spread to her lungs. She had been treated in the past for excessive parathyroid hormone levels.

Parathyroid hormone-related protein (PTHrP) expressed by non-malignant tissues and malignant tumors exhibits a complex posttranslational processing which is tissue- and isoform-specific. Rat insulinoma and Chinese hamster ovary cells contain a novel carboxy-terminal form of PTHrP. Cell lines comprising the three PTHrP transcripts produce a midregion form and a multiple amino terminal PTHrP secretory form.

Some cancer patients develop hypercalcemia, or elevated levels of calcium in their blood. Hypercalcemia is generally associated with a poor prognosis. The condition was known to result because the tumors produced a protein that is similar to parathyroid hormone and binds to parathyroid hormone receptors on normal cells. This protein, the parathyroid hormone-related protein (PTHRP), has been isolated and its gene cloned and sequenced. These developments have permitted the development of specific assays for PTHRP; little or no PTHRP is present in normal subjects, whereas the substance is elevated in patients with hypercalcemia due to cancer. The substance was normal in patients with other types of hypercalcemia. PTHRP is, however, elevated in both breast tissue and breast milk. Assays have been developed to detect specific portions of the PTHRP molecule. In particular, one detects the presence of the first 74 amino acids in the chain, and another detects the amino acids from position 109 to 138. In patients with chronic renal failure, levels of the first 74-amino acid chain were normal, but levels of the 109 to 138 chain were elevated, suggesting that the molecule may be split into pieces. This has been confirmed by using antibodies to remove the first piece from blood plasma. The second piece remained in the plasma, indicating that they must be separate. These assays may be especially valuable in the differential diagnosis of hypercalcemia due to cancer as opposed to other causes. (Consumer Summary produced by Reliance Medical Information, Inc.)

Experiments in vivo have established that tooth eruption fails in the absence of parathyroid hormone (PTH)-related protein (PTHrP) action in the microenvironment of the tooth because of the failure of osteoclastic bone resorption on the coronal tooth surface to form an eruption pathway. To elucidate the effects of PTHrP on osteoclast regulation in this environment, we established primary cultures of epithelial stellate reticulum cells and mesenchymal dental follicle (DF) cells surrounding the teeth. When cocultured, these cells are fully capable of supporting the formation of functional osteoclasts in the absence of added splenic osteoclasts precursors, osteoblasts, or vitamin D/PTH/PTHrP. Neutralizing the effects of PTHrP resulted in a decrease in the number of osteoclasts formed, suggesting that stellate reticulum-derived PTHrP drives osteoclast formation. DF cells were found to express functional PTH/PTHrP type I receptors, and conditioned media collected from PTHrP-treated DF cells were able to induce bone resorption in the fetal-rat long-bone assay. PTHrP treatment also induced an increase in osteoclast differentiation factor expression and a concomitant decrease in osteoclastogenesis inhibitory factor expression in DF cells. The addition of osteoclastogenesis inhibitory factor resulted in a decrease in the number of osteoclasts formed in the cocultures, suggesting that osteoclast formation is mediated by osteoclast differentiation factor. Thus, PTHrP seems to regulate osteoclast formation via mediation of the DF, in a manner analogous to the osteoblast-mediated process in the peripheral skeleton. The primary coculture system of dental crypt cells also offers a system for the study of osteoclast formation and regulation.

The modeling of long bone surfaces during linear growth is a key developmental process, but its regulation is poorly understood. We report here that parathyroid hormone-related peptide ( PTHr P) expressed in the fibrous layer of the periosteum ( PO) drives the osteoclastic ( OC) resorption that models the metaphyseal-diaphyseal junction ( MDJ) in the proximal tibia and fibula during linear growth. PTHr P was conditionally deleted (c KO) in the PO via Scleraxis gene targeting ( Scx- Cre). In the lateral tibia, c KO of PTHr P led to a failure of modeling, such that the normal concave MDJ was replaced by a mound-like deformity. This was accompanied by a failure to induce receptor activator of NF-kB ligand ( RANKL) and a 75% reduction in OC number ( P ≤ 0.001) on the cortical surface. The MDJ also displayed a curious threefold increase in endocortical osteoblast mineral apposition rate ( P ≤ 0.001) and a thickened cortex, suggesting some form of coupling of endocortical bone formation to events on the PO surface. Because it fuses distally, the fibula is modeled only proximally and does so at an extraordinary rate, with an anteromedial cortex in CD-1 mice that was so moth-eaten that a clear PO surface could not be identified. The c KO fibula displayed a remarkable phenotype, with a misshapen club-like metaphysis and an enlargement in the 3 D size of the entire bone, manifest as a 40-45% increase in the PO circumference at the MDJ ( P ≤ 0.001) as well as the mid-diaphysis ( P ≤ 0.001). These tibial and fibular phenotypes were reproduced in a Scx- Cre-driven RANKL c KO mouse. We conclude that PTHr P in the fibrous PO mediates the modeling of the MDJ of long bones during linear growth, and that in a highly susceptible system such as the fibula this surface modeling defines the size and shape of the entire bone. [ABSTRACT FROM AUTHOR]