Deficient/excess GH, dwarfism, gigantism, acromegaly, parathyroid glands, CaSR dysfunctions, calcium homeostasis, degenerative bone disorders, bone remodeling, osteoporosis, parathyroid hormone, osteoclast, Paget's disease of bone, bone tumors, PTHrP

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Colorado State University
Biomedical Science
BMS 460
D.Rao Veeramachaneni

25 October Deficiency of GH/GF-1: Dwarfism Shortened epiphyseal growth plate Reduction in the width of the hypertrophic zone results in a 30% decrease in the longitudinal growth of bone Laron syndrome, or Laron-type dwarfism, is an autosomal recessive disorder characterized by an insensitivity to GH. It is caused by a variant of the GH receptor – mainly associated with mutations in the gene for the GH receptor. These can result in defective hormone binding to the ectodomain or reduced efficiency of dimerization of the receptor after hormone occupancy. There are exceptionally low levels of IGF-1 and its principal carrier protein, IGF-binding protein 3. It causes short stature and a resistance to diabetes and cancer. Excess GH: Gigantism and Acromegaly Pituitary adenoma: functional somatotroph adenomas cause excess secretion of GH GH excess during childhood and puberty Linear and periosteal growth of long bones Cartilage, membranous bones, soft tissues also affected Post-pubertal GH excess: acromegaly Long bones do not grow in length but cartilage and membranous bones continue to grow Soft tissues become enlarged Acromegalic facies Protruding supraorbital ridges Enlarged noses Coarse facial features Prognathia Headaches Thickened calvaria Hypertension Hepatomegaly Insulin resistance (diabetes) Large hands Thickened skin Impotence and loss of libido (amenorrhea in women) Hyperostosis Degenerative joint disease Peripheral neuropathy (nerve compression) Large feet and heel pad Acromegaly lab ↑ GH ↑ IGF-1 ↑ insulin ↑ Ca , P - ↑ glucose ACTH (↑ or ↓) 99% of total body Ca (~1 kg) is in bones Parathyroid Glands Found on the posterior surface of the thyroid gland, between its capsule and the surrounding cervical connective tissue. In addition to the four parathyroid glands, accessory glands may be found in the mediastinum or in the neck. The four parathyroid glands derive from the third and fourth branchial pouches. The third branchial pouch differentiates into the inferior parathyroid glands and the thymus. The fourth branchial pouch develops into the superior parathyroid glands and the ultimobranchial body. DiGeorge Syndrome – Absence of parathyroid glands and thymus 1:4000 Caused by the deletion of a small piece of chromosome 22 Features vary widely and may include birth defects The parathyroid gland consists of two cell types: chief cells, which secrete parathyroid hormone (PTH), and oyxphil cells, rich in mitochondria, representing probably a transitional form of chief cells. Cells are arranged in a cordlike arrangement, but a follicular-like arrangement can also be observed. Processing of parathyroid hormone Preproparathyroid hormone precursor is synthesized in rough endoplasmic reticulum and processed to proparathyroid hormone to PTH. 2+ Chief cells synthesize and secrete PTH. Ca -sensing receptor (CaSR) is a seven- transmembrane-spanning receptor coupled to G protein on the plasma membrane of the parathyroid cell. A reduction in serum calcium levels activates CaSR and increases PTH secretion, with a resultant increase in serum calcium. Oxyphil cells appear after puberty and increase in number with age. They contain abundant mitochondria, which give this cell type an acidophilic staining in hematoxylin- eosin preparations. The rough endoplasmic reticulum and Golgi apparatus are not prominent. Oxyphil cells do not secrete PTH. CaSR Dysfunctions: Sequelae Mutations of CaSR Inactivating mutations of one allele of CaSR Prevent chief cells from sensing increase in serum [Ca] → ↑ PTH Familial benign hypercalcemia (familial hypocalciuric hypercalciumia) Can be severe if both alleles are inactivated Requires immediate parathyroidectomy in newborns Activating mutations Chief cells assume serum [Ca] is elevated when it is not → ↓ PTH Hypocalcemia Treat with PTH Autoimmunity: CaSR can be a target of autoimmunity Either inactivate CaSR (syndrome similar to familial benign hypercalcemia) or activate CaSR (hypoparathyroidism) 2+ Normally, when the serum [Ca ] decreases, the secretion of PTH is stimulated, resulting in an increase in serum [Ca ]2+ ↑ PTH → ↑ serum [Ca ] 2+ ↑ serum [Ca ]+ No PTH release 2+ Serum Ca binding to the extracellular region of the CaSR triggers intracellular signals suppressing PTH secretion ↓ serum [Ca ]+ PTH release 2+ A reduction in serum Ca activates CaSR and increases PTH secretion, with a resultant increase in serum Ca 2+ The Ca sensing receptor (CaSR) is associated to G protein in the plasma membrane of chief cells Calcium Homeostasis The role of parathyroid hormone ↓ serum calcium level → ↑ PTH secretion → PTH promotes calcium and phosphate resorption from bone, calcium reabsorption and phosphate excretion from the renal tubule, calcium absorption from the GI tract → ↑ serum calcium level → ↓ PTH secretion ↓ plasma calcium → parathyroid glands → ↑ parathyroid hormone secretion → ↑ plasma parathyroid hormone Bone → ↑ resorption → ↑ release of calcium into plasma → restoration of plasma calcium levels turned normal Kidneys → ↑ calcium reabsorption, ↑ 1,25-(OH) D for2ation ↑ calcium reabsorption → ↓ urinary excretion of calcium → restoration of plasma calcium levels toward normal ↑1,25-(OH) D2formation → ↑ plasma 1,25-(OH) D → in2estine → ↑ calcium absorption into blood → restoration of plasma calcium levels toward normal The role of vitamin D activation Plasma vitamin D sources Dietary vitamin D 2r D 3 Sunlight → skin: 7-dehydrocholesterol → vitamin D 3 Plasma vitamin D → liver: 25-hydroxylase converts vitamin D to 25-OH D → kidneys: 1-hydroxylase converts 25-OH D to 1,25-(OH) D → pl2sma 1,25-(OH) D 2 → GI tract: ↑ absorption of calcium (and phosphate) into blood Calcium balance in the body Total body calcium = intake – output Components of total serum calcium Bound to albumin Bound to phosphorus citrate Free In small intestine Dietary calcium → Ca → calcium in feces Ca moves in ECF via calcitriol [1,25-(OH) Vit D3] (PTH, prolactin) 2 2+ [Ca ] 2.5 mM Moves into cells via electrochemical gradient Moves to kidneys via passive filtration Moves to bone via calcitonin Bone Moves back to ECF via PTH, calcitriol, cortisol Cells 2+ [free Ca ] 1 μM Moves back to ECF via active transport Kidney Moves back to ECF via PTH Inhibited from moving to ECF via calcitonin Ca in kidney tubules → Ca in urine Degenerative Bone Disorders Ossification includes growth, modeling, and remodeling of the bone, processes mediated by osteoblasts and osteoclasts under the control of local regulatory factors and blood- borne signaling molecules, including parathyroid hormone and vitamin D3. Rickets and osteomalacia are a group of bone diseases characterized by a defect in the mineralization of the bone matrix (osteoid), most often caused by a lack of vitamin D3 Rickets is observed in children and produces skeletal deformities Osteomalacia is observed in adults and is caused by poor mineralization of the bone matrix Bone Remodeling Consists of the replacement of newly formed and old bone by a resorption-production sequence, which depends on closely coupled activities of osteoblasts and osteoclasts Continuous process throughout life, occurs at random locations Establish the optimum of bone strength by repairing macroscopic damage (microcracking), maintain calcium homeostasis Activation Osteoclast precursors are recruited to the haversian canal and differentiate into osteoclasts. Osteoclasts are lining the bone lamella facing the canal and start the bone resorption process of the inner lamella and consecutive lamellae toward the outer lamella Interstitial lamellae are residuals of the remodeling osteon. Resorption Additional osteoclast precursors are recruited as lamellar resorption progresses slightly beyond the boundary of the original osteon. When osteoclasts stop removing bone, osteoblasts appear (osteoclast to osteoblast reversal) Reversal Osteoblasts reverse the resorption process by organizing a layer inside the reabsorption cavity and starting to secrete osteoid. The cement line indicates the boundary of the newly organized lamella. New bone lamellae continue to be deposited toward the center of the osteon. Formation Osteoblasts continue laying down bone and eventually become trapped within the mineralized bone matrix and become osteocytes. A new osteon or haversian system is formed. In osteoporosis, more bone is reabsorbed than is subsequently produced. Osteoporosis Bone resorption exceeds bone deposition Both matrix and minerals are lost Estrogen normally inhibits production of osteoclasts; enhances osteoblasts Estrogen deficiency leads to ↑ osteoclastic activity ↓ osteoblastic activity Increased resorption of bone by osteoclasts Decreased formation of bone by osteoblasts Hypercortisolism: Glucocorticoids increased production of RANKL but decrease the production of osteoprotegerin (by osteoblasts and thereby increase osteoclastogenesis) and thus promote bone loss Epidemiology Most common metabolic abnormality of bone Loss of both organic bone matrix
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