Periparturient Mineral Metabolism: Implications to Health and Productivity

Abstract

Mineral metabolism, in particular Ca, and to a lesser extent phosphorus (P) and magnesium (Mg), is altered with the onset of lactation because of extensive irreversible loss to synthesize colostrum and milk. The transient reduction in the concentration of Ca in blood, particularly when it lasts days, increases the risk of mineral-related disorders such as hypocalcemia and, to a lesser extent, hypophosphatemia. Although the incidence of clinical hypocalcemia can be reduced by prepartum dietary interventions, subclinical hypocalcemia remains prevalent, affecting up to 60% of the dairy cows in the first 3 d postpartum. More importantly, strong associations exist between hypocalcemia and increased susceptibility to other peripartum diseases and impaired reproductive performance. Mechanistic experiments have demonstrated the role of Ca on innate immune response in dairy cows, which presumably predisposes them to other diseases. Hypocalcemia is not related to inadequate Ca intake as prepartum diets marginal to deficient in Ca reduce the risk of the disease. Therefore, the understanding of how Ca homeostasis is regulated, in particular how calciotropic hormones such as parathyroid hormone and 1,25-dihydroxyvitamin D₃, affect blood Ca concentrations, gastrointestinal Ca absorption, bone remodeling, and renal excretion of Ca become critical to develop novel strategies to prevent mineral imbalances either by nutritional or pharmacological interventions. A common method to reduce the risk of hypocalcemia is the manipulation of the prepartum dietary cation-anion difference. Feeding acidogenic diets not only improves Ca homeostasis and reduces hypocalcemia, but also reduces the risk of uterine diseases and improves productive performance. Feeding diets that induce a negative Ca balance in the last weeks of gestation also reduce the risk of clinical hypocalcemia, and recent work shows that the incorporation of mineral sequestering agents, presumably by reducing the absorption of P and Ca prepartum, increases blood Ca at calving, although benefits to production and health remain to be shown. Alternative strategies to minimize subclinical hypocalcemia with the use of vitamin D metabolites either fed prepartum or as a pharmacological agent administered immediately after calving have shown promising results in reducing hypocalcemia and altering immune cell function, which might prove efficacious to prevent diseases in early lactation. This review summarizes the current understanding of Ca homeostasis around parturition, the limited knowledge of the exact mechanisms for gastrointestinal Ca absorption in bovine, the implications of hypocalcemia on the health of dairy cows, and discusses the methods to minimize the risk of hypocalcemia and their impacts on productive performance and health in dairy cows.

Keywords: calcium; dairy cow; dietary cation-anion difference; mineral.

Figure 1

Proposed gastrointestinal absorption of calcium (Ca) in bovine. (A), in vitro studies suggest the presence of active transport of Ca in the rumen epithelium; however, it remains unclear the exact mechanism and the Ca channels involved in the apical absorption of Ca. The expression of transient receptor potential vanilloid 6 (TRPV6), the classical channel present in enterocytes, is poorly expressed in rumen epithelium. Alternatively, TRPV3, TRPV4, and a Ca/H⁺ exchanger are potential channels involved in Ca uptake at the apical membrane. The presence of vitamin D receptors and how 1,25-dihydroxyvitamin D₃ regulates Ca transport in the rumen remains unknown. Likewise, the presence of calbindin-D_9k is uncertain. At the basolateral membrane, the ruminal epithelia express plasma membrane Ca ATPase (PMCA1b), which extrudes Ca from the cell; however, the presence of sodium (Na) Ca exchanger 1 (NCX1) needs to be determined. (B) On the apical membrane of enterocytes, TRPV6 is primarily responsible for the uptake of Ca into the cell. Once in the cytosol, Ca binds calbindin-D_9k, and the complex is translocated to the basolateral membrane. On the basolateral membrane, Ca is released from calbindin-D_9k and can be extruded from the cell through the NCX1, which is energy independent; however, because it increases the cytosolic concentration of Na, Na/K-ATPase uses ATP to maintain Na balance by exchanging Na with potassium (K), thus maintaining the cell potential. In addition, Ca can be extruded from the cell by the PMCA1b incurring in ATP expenditure. 1,25-dihydroxyvitamin D₃ plays a key role in Ca transport in the enterocyte by stimulating mRNA and protein expression of TRPV6, calbindin-D_9k, and NCX1. Calcium absorption also occurs via paracellular transport in favor of the chemical gradient, but recent evidence suggests some control of tight junction proteins claudin 2 an 12 by vitamin D, which can affect the passive flow of Ca from the lumen of the gastrointestinal tract to the interstitial space and venules draining the gastrointestinal tract. Arrows point to the direction of flow of a chemical element, the side of the cell if apical or basolateral, or the effect of a stimulus (hormone or activation of gene) on multiple cellular responses. Arrows with positive symbols indicate downstream stimulation. Different shapes (circles, squares, triangles) with respective colors represent different minerals in and out of the cell. Pocket shapes represent calbindin-D_9k protein transporting Ca²⁺ within the cytosol. Channels in the apical and basolateral membranes represent the different ion channels responsible for Ca²⁺ flux in and out of the cell or for maintenance of cell potential.

Figure 2

Mechanisms of metabolic acidosis influencing calcium (Ca) homeostasis in bovine. (A) Cations such as Ca²⁺ and H⁺ can bind to negatively charged proteins such as albumin. During metabolic acidosis, the increased concentration of H⁺ competes with Ca²⁺ to bind to those proteins, and Ca²⁺ is released. Moreover, Ca binds to anions, such as bicarbonate, and the reduced concentration of bicarbonate during metabolic acidosis results in an increased concentration of Ca²⁺ in the blood. (B) In the Chief cells of the parathyroid gland, metabolic acidosis increases the synthesis and release of parathyroid hormone (PTH). (C) Tissue responsiveness to PTH is increased during metabolic acidosis; conformational changes in the receptor increase the ability of PTH to bind, thereby increasing the effects of PTH on target cells. (D) In the proximal tubule cells of the kidney, PTH stimulates the expression of 1α-hydroxylase in the mitochondria, resulting in greater conversion of 25-hydroxyvitamin D₃ to 1,25-dihydroxyvitamin D₃. In the distal convoluted tubule, 1,25-dihydroxyvitamin D₃ stimulates the expression of transient receptor potential vanilloid 5 (TRPV5), calbindin-D_28k, sodium Ca exchanger 1 (NCX1), which is expected to increase reabsorption of Ca from the urinary filtrate; however, the resulting tubular acidosis induced by increased concentration of H⁺ in the filtrate blocks the transport of Ca across the TRPV5 resulting in increased urinary loss of Ca. (E), absorption of Ca in the gastrointestinal tract (GIT) differs between the rumen and small intestine (see Figure 1). In the small intestine, 1,25-dihydroxyvitamin D₃ increases the expression of TRPV6, calbindin-D_9k, NCX1, and claudins 2/12; consequently, transcellular and paracellular transport of Ca is increased. Effects of 1,25-dihydroxyvitamin D₃ on pre-duodenal absorption of Ca remain to be elucidated. (F), increased concentration of H⁺ stimulates prostaglandin (PG) E synthesis by osteoblast, which stimulates receptor activator of nuclear factor κβ ligand (RANKL) synthesis in adjacent osteoblasts. Additionally, PTH and 1,25-dihydroxyvitamin D₃ stimulate RANKL expression and suppress the expression of osteoprotegerin (OPG). Reduced OPG allows RANKL to bind to RANK on osteoclast precursors and promote the maturation of those cells. Mature osteoclasts are stimulated by 1,25-dihydroxyvitamin D₃ promoting the expression of carbonic anhydrase II (CAII), which produces bicarbonate and H⁺ from water and carbon dioxide. The increased H⁺ is secreted into the bone lacunae which facilitates collagen degradation by cathepsin K releasing Ca²⁺ from bone. Within each panel, positive and negative symbols indicate downstream stimulation and repression, respectively.

Figure 3

Diagram depicting the associations among diseases in which hypocalcemia has been shown to play a central role either through epidemiological studies or mechanistic experiments. References are included [13,14,16,31,44,147,148,151,152,153,154,155,156,157,158,159,160,161,162]. Continuous lines depict links among diseases. Dashed blue lines depict proposed mechanisms linking immune function and some diseases. Arrows before each disease indicate if hypocalcemia is associated with an increase (arrow up) or decrease/delay (arrow down) in the particular response. DMI = dry matter intake; GIT = gastrointestinal tract; RFM = retained fetal membranes.