Lecture 1 - Endocrine Control of Calcium Homeostasis PDF

**[Lecture 1 - Endocrine Control of Calcium Homeostasis ]** **Calciotropic Hormones & Receptors** **Importance of Calcium: Essential for bone formation, neuromuscular function, and intracellular signaling.\ Forms and Location of Calcium in Humans:** **Insoluble calcium (99%) in bones and teeth.\...

**[Lecture 1 - Endocrine Control of Calcium Homeostasis ]** **Calciotropic Hormones & Receptors** **Importance of Calcium: Essential for bone formation, neuromuscular function, and intracellular signaling.\ Forms and Location of Calcium in Humans:** **Insoluble calcium (99%) in bones and teeth.\ Extracellular soluble calcium (1%) in blood and extracellular fluid (ECF).\ Intracellular calcium is mostly insoluble within organelles like ER, mitochondria.\ Normal Calcium Concentration: Requires regulation within a narrow range; deviations can cause neuromuscular issues and impact cardiac function.\ Calciotropic Hormones and Their Sources** **Primary Hormones in Calcium Homeostasis:** **Parathyroid Hormone (PTH):** **Parathyroid Hormone (PTH) Mechanism of Action** **PTH is a key regulator of calcium homeostasis, primarily secreted by the chief cells of the parathyroid glands in response to low serum calcium levels. Its actions can be summarised as follows:** **Bone Resorption: PTH stimulates osteoclast activity indirectly by binding to osteoblasts, which then release RANKL (Receptor Activator of Nuclear factor Kappa-Β Ligand). This leads to increased bone resorption and release of calcium into the bloodstream.** **Renal Reabsorption: In the kidneys, PTH enhances tubular reabsorption of calcium in the distal convoluted tubule while promoting phosphate excretion in the proximal tubule. This dual action helps to increase serum calcium levels while decreasing phosphate levels.** **Intestinal Absorption: PTH indirectly increases intestinal calcium absorption by stimulating the conversion of vitamin D to its active form (calcitriol) in the kidneys. Calcitriol enhances intestinal absorption of calcium and phosphate.** **Overall, PTH acts synergistically through these mechanisms to elevate serum calcium levels, counteracting hypocalcaemia effectively.** **\ Effects of PTH** **Increases blood calcium levels, stimulates osteoclast activity, enhances renal reabsorption of calcium.\ Increases calcium levels by stimulating bone resorption, releasing calcium from bones and enhances renal calcium reabsorption. Activates vitamin D in the kidneys, aiding calcium absorption in the intestines.\ PTH secretion is inversely proportional to serum Ca2+; low plasma \[Ca2+\]=⬆️PTH secretion, high plasma \[Ca2+\] = ⬇️PTH secretion.\ Steep sigmoidal relationship between maximal PTH release and Ionised Ca2+ indicates tightly regulated plasma Ca2+.\ Feedback regulation via Ca2+-sensing receptor (CaR), a GPCR responsive to Ca2+o (and Mg2+o). CaR is also present in kidneys where it limits calcium reabsorption. Monitors blood Ca2+ levels continuously & serves as the ultimate control point for Ca2+ homeostasis.\ Vitamin D (1,25(OH)₂D₃):** **Synthesised in skin (from UV exposure) or obtained from diet.\ Increases serum calcium by enhancing intestinal calcium absorption and promoting bone resorption.\ Requires conversion to active form in the liver and kidneys.\ Effects of 1,25(OH)2D3** **The final step is catalysed by 1a- Hydroxylase primarily in the renal Proximal Tubule.\ 1,25(OH)2D3 can ­ net intestinal Ca2+ uptake from 200 to as much as 600 mg / day. It ­ calbindin expression (D9k and D28k - see later lecture).\ 1,25(OH)2D3 can also ­ serum Ca2+ levels by bone resorption and renal Ca2+ reabsorption (as for PTH).\ It is not soluble in the blood so it need to be transported using a soluble protein.Vit D3 (& its --OH derivatives) are lipid soluble ® carried in plasma bound to specific globulin VitD binding protein (DBP).\ Calcitonin (optional in some species):** **Reduces blood calcium by inhibiting osteoclast activity, leading to decreased bone resorption.\ Mechanism of Calcium Regulation** **PTH and Calcium-Sensing Receptor (CaR):** **CaR is a GPCR that senses extracellular calcium levels.\ High calcium levels activate CaR, inhibiting PTH release.\ Low calcium levels reduce CaR activation, stimulating PTH release.\ Vitamin D Activation Pathway:** **UVB initiates conversion of 7-dehydrocholesterol to pre-vitamin D₃ in the skin.\ Converted to 25(OH)D₃ in the liver and then to active 1,25(OH)₂D₃ in the kidneys.\ Vitamin D Receptors (VDRs)** **Location and Structure:** **VDRs are nuclear receptors, located in the nuclei of target cells, particularly within the intestine, kidney, and bone. They are part of the steroid hormone receptor family and regulate gene expression in response to vitamin D binding.\ Mechanism of Action:** **Vitamin D Binding: The active form of vitamin D, 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), binds to VDRs within the cell nucleus.\ Gene Regulation: Once activated, the VDR forms a complex with the retinoid X receptor (RXR), which then binds to specific DNA sequences known as vitamin D response elements (VDREs) on target genes.\ Transcriptional Effects: This VDR-RXR complex initiates the transcription of vitamin D-responsive genes, leading to increased synthesis of proteins involved in calcium absorption, bone mineralization, and cellular differentiation.\ Role in Calcium Homeostasis:** **Intestinal Calcium Absorption: VDRs are critical in the small intestine, where they regulate the synthesis of proteins like TRPV6 (a calcium channel), calbindin, and PMCA (a calcium pump), facilitating both active and passive calcium absorption.\ Renal Calcium Reabsorption: VDRs also play a role in the kidneys, where they help maintain serum calcium levels by promoting calcium reabsorption in the distal convoluted tubules.\ Vitamin D and Bone Health:** **VDR activation is essential for bone mineralization. It indirectly supports bone resorption by maintaining serum calcium and phosphate levels, necessary for bone formation and strength.\ Insufficient VDR activity, due to either vitamin D deficiency or VDR mutations, can result in bone diseases like rickets or osteomalacia due to poor calcium absorption.\ Clinical Relevance of VDR Mutations:** **Mutations in the VDR gene can lead to conditions such as Vitamin D-dependent rickets type II (VDDR II), characterized by impaired calcium absorption and bone mineralization despite adequate vitamin D levels.\ Symptoms of VDDR II include bone deformities, growth retardation, and hypocalcemia.\ Vitamin D Synthesis and Geographical Considerations:** **VDR activity depends on sufficient levels of 1,25(OH)₂D₃, which in turn depends on adequate sunlight exposure (UVB).\ Geographic regions with low UVB exposure (e.g., UK, particularly during winter months) may have populations with low vitamin D levels, impacting VDR activity and increasing the risk of bone and immune-related disorders.\ Research and Therapeutic Applications:** **VDR is a target for research in osteoporosis and autoimmune diseases, given its role in regulating immune responses and maintaining bone density.\ Synthetic vitamin D analogs and VDR agonists are being explored for their potential to treat conditions related to calcium homeostasis and inflammation.\ Calcium Absorption in the Intestines:** **Active transport (via TRPV6, calbindin, PMCA) requires 1,25(OH)₂D₃, especially in the duodenum. This proteins are regulated by vitamin D\ Passive transport is paracellular, occurring in the small intestine.\ Renal Reabsorption:** **Calcium reabsorption in the kidney's distal convoluted tubule (DCT) is enhanced by PTH.\ Calcium Disorders and Clinical Indicators** - - - - - - - - - - - - - - **High calcium and phosphate levels can lead to calciphylaxis, a serious complication involving vascular calcification.** ### **Calciotropic Hormones and Receptors** **Calcium is critical for bone formation, neuromuscular function, and intracellular signaling. Most calcium is stored as insoluble hydroxyapatite in bones and teeth (99%), with a small soluble fraction in extracellular fluid and within organelles. The body regulates calcium tightly; low levels (hypocalcemia) can cause tetany, while high levels (hypercalcemia) may lead to arrhythmias. Parathyroid hormone (PTH) increases serum calcium by stimulating bone resorption, renal reabsorption, and calcitriol production for enhanced intestinal absorption. Vitamin D, activated via UV exposure and hydroxylation in the liver and kidneys, increases intestinal calcium absorption and supports PTH actions in bone and kidney. Calcitonin, though vestigial in humans, inhibits osteoclast activity and reduces serum calcium.** ### **Calcium Regulation** **The body maintains calcium balance through dietary intake, bone turnover, and renal filtration. Bone acts as a reservoir, with rapid exchange of calcium into and out of a mobilizable pool, while structural remodeling occurs more slowly. Daily dietary calcium absorption is inefficient (\~30%), resulting in a net uptake of \~200 mg, which is matched by renal excretion. PTH dynamically regulates calcium levels through feedback via the calcium-sensing receptor (CaR), ensuring precise control of serum calcium. Sustained PTH elevation demineralizes bone, while pulsatile PTH promotes bone formation, as seen with therapies like teriparatide.** ### **Vitamin D and Calcium Absorption** **Vitamin D, synthesized in the skin and activated in the liver and kidney, enhances intestinal calcium absorption via TRPV6 channels and calbindin proteins, which are regulated by vitamin D. Insufficient vitamin D, common in regions with low sunlight exposure (e.g., UK), leads to bone diseases like rickets and osteoporosis. Vitamin D also supports PTH in increasing renal calcium reabsorption and bone resorption but uniquely enhances intestinal calcium uptake due to its receptor expression in the gut.** ### **Disorders of Calcium Homeostasis** **Hypocalcemia manifests as muscle spasms, tetany (e.g., Trousseau's and Chvostek's signs), and potentially cardiac complications, while hypercalcemia causes lethargy, arrhythmias, and death. Primary hyperparathyroidism results in excessive PTH secretion, often due to adenomas, causing hypercalcemia and bone loss. Secondary hyperparathyroidism, typically associated with chronic kidney disease, increases PTH due to low calcium or high phosphate levels. Treatments include calcimimetics to reduce PTH secretion and calcilytics for gain-of-function mutations in CaR.** ### **Calcium Receptor (CaR)** **The CaR, a G-protein coupled receptor, regulates PTH secretion through feedback on extracellular calcium levels. It integrates signals from divalent cations (calcium, magnesium), amino acids, and polyamines. Loss-of-function mutations cause hypercalcemia (e.g., familial hypocalciuric hypercalcemia), while gain-of-function mutations lead to hypocalcemia. Calcimimetics activate the receptor to suppress PTH, while calcilytics reduce its sensitivity, allowing PTH to increase serum calcium.** ### **Osteoporosis** **Postmenopausal osteoporosis, caused by estrogen deficiency, disrupts bone remodeling by increasing osteoclast activity and reducing osteoblast function. This results in weakened bones prone to fractures, especially in the hip, spine, and wrist. Treatments include anti-resorptive agents like bisphosphonates and SERMs, which inhibit bone breakdown, and anabolic therapies like teriparatide, which promote bone formation. Calcium and vitamin D supplementation are foundational to maintaining bone health and preventing secondary hyperparathyroidism.**