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Parathyroid hormone-related protein shares similarities in sequence and function with the endocrine hormone, parathyroid hormone. However, unlike parathyroid hormone, a product of the parathyroid glands, parathyroid hormone-related protein has a wide distribution in tissues, including the mammary gland. Although during pregnancy the expression of parathyroid hormone-related protein in the mammary gland is low, following birth, protein levels rise sharply in the gland in response to elevations in serum prolactin. Large amounts of parathyroid hormone-related protein are secreted into milk, suggesting a possible role in the neonate. Transient phosphaturia and elevations of parathyroid hormone-related protein in mammary vein plasma support a possible endocrine function for parathyroid hormone-related protein during lactation. Recent evidence suggests a local function for parathyroid hormone-related protein in the lactating mammary gland, and evidence exists that parathyroid hormone-related protein stimulates calcium secretion by the goat mammary gland. Parathyroid hormone-related protein, a putative vasodilator, is produced by the external nutrient vasculature of the mammary gland, and levels within this tissue are regulated during lactation. Infusion of parathyroid hormone-related protein into the ovine mammary artery increases gland blood flow, suggesting a role for the protein in modulation of mammary gland hemodynamics. Regulation of parathyroid hormone-related protein synthesis by the lactating gland, together with the protein's actions on regional blood flow and calcium secretion, support an important function in the mammary gland during lactogenesis.

PTH-related protein (PTHrP) is found in high concentrations in the milk of various mammals. However, little is known about the regulation of PTHrP production or the physiological role(s) of PTHrP in the mammary glands. To address these questions, we examined in lactating rats 1) the longitudinal changes in PTHrP concentrations in milk and PTHrP mRNA levels in the mammary glands throughout lactation, 2) the effects of the nonsuckling interval on milk PTHrP concentration, and 3) the correlation between PTHrP and calcium concentrations in milk. PTHrP concentrations in milk, measured by RIA and in vitro bioassay, increased with the duration of lactation. The maximal concentrations of PTHrP (observed between days 19-21 of lactation in rats milked serially) were 4.8- to 8.0-fold higher than the concentrations on day 7. PTHrP mRNA levels in the mammary glands also increased during the late stages of lactation. The longitudinal changes in calcium concentrations in milk were small and did not parallel the changes in PTHrP. When pups were removed from the mother for 4-24 h, milk PTHrP decreased while calcium increased in a time-dependent manner. As a whole, calcium concentrations in milk did not correlate with PTHrP throughout lactation. These data suggest that the production and secretion of PTHrP into milk are regulated independently of the other major milk proteins by a factor(s) that changes with progression of lactation and in relation to suckling status.

A survey of rat tissues by RNA analysis, aimed at uncovering the physiological function of the parathyroid hormone-like peptide (PTH-LP) associated with hypercalcemia of malignancy, revealed the presence of a 1.5-kilobase messenger RNA encoding this peptide in lactating mammary glands. PTH-LP messenger RNA is expressed in mammary tissue only during lactation; it appears and disappears rapidly (2 to 4 hours) as a function of the sucking stimulus. The identity of this messenger RNA was confirmed by cloning the rat PTH-LP complementary DNA, which predicts a peptide with strong similarity to the human homolog. Moreover, extracts from lactating mammary tissue stimulated parathyroid hormone-dependent adenylate cyclase. These findings suggest that PTH-LP plays a physiological role in lactation, possibly as a hormone for the mobilization or transfer (or both) of calcium to the milk.