BCM 1.06 Bone Biochemistry.pdf

BIOCHEMISTRY Bone Biochemistry BLOCK 1 Dr. Ann Visda, MD | August 22, 2024...

BIOCHEMISTRY Bone Biochemistry BLOCK 1 Dr. Ann Visda, MD | August 22, 2024 Trans 1.06 OVERVIEW B. Compartments of Bone I. Bone Overview IV. Bone Conditions A. Functions of Bone A. Osteoporosis B. Compartments of Bone B. Osteopetrosis C. Composition of Bone C. Rickets II. Bone cell types D. Renal Osteodystrophy A. Osteoblasts E. Osteogenesis Imperfecta B. Osteocytes V. Summary C. Osteoclasts VI. References III. Bone Remodeling A. Phases B. Factors LEGEND : Important Information : Additional Information ABBREVIATIONS PTH Parathyroid Hormone RANKL Receptor Activator of Nuclear Factor κβ Ligand RANK Receptor Activator of Nuclear Factor κβ OPG Osteoprotegerin FSH Follicle Stimulating Hormone IL-1 Interleukin 1 TNF Tumor Necrosis Factor M-CSF Macrophage Colony Stimulating Hormone Colony-stimulating factor 1 receptor (CSF1R a.k.a C- C-FMS FMS) Figure 1. Compartments of Bone[Junqueira Basic Histology]. LEARNING OBJECTIVES Cortical Bone Enumerate the functions of the bone. ○ Provides mechanical function and is protective Discuss and explain the different bone cell types and their ○ A dense bone that serves as a protective layer roles in bone remodeling Higher strength and rigidity than spongy bone Discuss the role of PTH, Vitamin D, and calcitonin in bone ○ Found outer to the cancellous bone metabolism ○ 4% renewed annually in typical healthy adult[Harper’s p. 614] Discuss the pathophysiology, clinical manifestations, and Trabecular Bone management of bone related diseases and conditions. ○ Provides strength and the majority of the metabolic function I. BONE OVERVIEW ○ Major site of bone remodelling and hematopoiesis A. Functions of Bone ○ Light and porous; gives a honeycomb appearance A highly dynamic specialized living tissue ○ Provides structural support and flexibility ○ Continuously resorbed by osteoclasts and neoformed by ○ Trabeculae is a three dimensional lattice work arranged osteoblasts to provide strength to the bone Plays a vital role in movement, support, and protection of soft Arrangement of the trabeculae make it resistant to tissues in the body. mechanical stress ○ Has sites of attachment for muscles Contains bone marrow Site of storage for inorganic elements (calcium and ○ 20% renewed annually in typical healthy adult[Harper’s p. 614] phosphate) in the body Periosteum Houses the bone marrow ○ Covers the surface of the bone except at the articular ○ Bone marrow is responsible for the continuous supply of cartilages[2028 Trans] red blood cells ○ Fibrous outer membrane Can undergo bone remodeling Provides site of attachment for tendons and ○ Bone remodeling is a process where old bone is removed ligaments or resorbed and replaced by new tissue Functions as bone protection ○ Occurs when reshaping bones after fracture or when ○ Inner cellular layer repairing micro-fractures Houses progenitor stem cells (Osteoblasts & Chondroblasts) Osteoblasts - secrete bone matrix Chondroblasts - produce cartilage Medullary Cavity ○ Hollow region of the diaphysis; contains bone marrow ○ Lined by spongy bone Page 1 of 13 | TH: MILLORA, I. | BCM TG 3 | ALCALA, ANGELES, GO, LIZARES, PULMONES, SY  BCM 1.06 Bone Biochemistry Osteons Origin: Mesenchymal Stem Cells (MSC) ○ Contains haversian canals ○ These are a type of stem cells that able to produce cells For blood supply and innervation of bones, muscles, and fat[Karp’s Cell Biology] Lamellae Round cells with a large nucleus, many mitochondria, and a ○ Concentric rings that make up the bone matrix well-developed Golgi apparatus ○ Organic Portion (Protein) Cell membranes contain alkaline phosphatase Type I collagen: Major protein (68%) ○ Enzyme that generates phosphate ions from organic Type V collagen and other noncollagen proteins are phosphates[Harper’s p. 612] also present in small amounts. ○ Phosphate plays a role in bone growth and mineralization Believed to play an active part in the mineralization Have vesicles that contain calcium and phosphates process. ○ Important in mineralization of bone by formation of Noncollagen proteins: Small proteoglycans, hydroxyapatite multiadhesive glycoproteins, osteoprotegerin May also contain acidic phosphoproteins sialoprotein and For elasticity, tensile strength and response to osteopontin pulling forces ○ Nucleation sites of hydroxyapatite crystal formation ○ Inorganic Portion (Mineral) ○ For binding calcium and providing an initial scaffold for Approximately 99% of body’s calcium is stored in mineralization the bone[Harper’s p. 612] Have receptors for PTH and Vitamin D For rigidity, hardness, and strength in compression ○ In cases of hypocalcemia, PTH and Vitamin D act on osteoblasts to increase bone resorption and induces C. Composition of Bone enhanced expression of RANKL that stimulates Cells (10%) osteoclast development Matrix Osteoclasts releases calcium from bone ○ Inorganic (60%) ○ Vitamin D also increases absorption of calcium in the Mineral crystals (Hydroxyapatite) [ Ca10(PO4)6(OH)2 ] intestines Note: Hydroxyapatite requires both Calcium (Ca2+) and Phosphate (PO43-) Following bone resorption: Na, Mg, HCO3, Fl (Sodium, Magnesium, bicarbonate, fluoride) ○ Secrete osteoid seam to fill in lacunae created by ○ Organic (30%) osteoclasts Type I collagen (68%) Calcium and phosphate deposit on the seam, forming Other proteins (10%) hydroxyapatite Lipids and Glycosaminoglycans (1-2%) ○ Osteoblasts that get trapped in the lacunae turn into osteocytes TP Note: In Doc’s lecture, the type I collagen percentage is 68%. But Harper states that it is 90-95%. II. BONE CELL TYPES Bone lining cells Osteocytes Osteoclasts Osteoblasts A. Osteoblasts Figure 3. Osteoid seam MECHANISMS INVOLVED IN MINERALIZATION[Harper’s p. 614] Tissue nonspecific alkaline phosphatase (TNAP) ○ An isoenzyme of alkaline phosphatase ○ Hydrolyzes inorganic pyrophosphate Inorganic pyrophosphate inhibits mineralization process Matrix vesicles containing calcium and phosphate ○ Involved in the formation of hydroxyapatite Type I collagen ○ Assembles into fibers that form the structural and mechanical scaffold of bone Acidic phosphoproteins (bone sialoprotein and Figure 2. Osteoblasts osteopontin) ○ Acts as sites of nucleation Role: Bone Formation/Deposition ○ Binds calcium and may provide initial scaffold for ○ Control mineralization by regulating the passage of mineralization calcium (Ca2+) and phosphate (PO43-) ions across their surface membranes Page 2 of 13 | TH: MILLORA, I. | BCM TG 3 | ALCALA, ANGELES, GO, LIZARES, PULMONES, SY  BCM 1.06 Bone Biochemistry Osteoblastogenesis Function: bone resorption ○ Has an apical membrane that contains a ruffled border responsible for resorption Allows translocation of protons/hydrogen ions from cell and into bone matrix using a hydrogen (H+) pump [Harper’s p. 613] H ions, when exposed to chloride ions (Cl-), produce + hydrochloric acid (HCl) into the extracellular compartment of the bone surface ↪ : HCl is not prduced as is inside the cell because this can lead to cell death. The cell releases the ingredients in the matrix which then forms the acidic compound outside the cell. For simplicity, Figure 4. Osteoblastogenesis we can just say that the cell “secretes” the HCl HCl is secreted across the ruffled border into the Process of Cell differentiation resorption area, lowering the local pH to 4.0 or less ○ : Definition [Basic version]: The transformation of cells ↪ Low pH increases the solubility of hydroxyapatite, from non-specialized to specialized helping its breakdown into Ca2+, H2CO3, PO43-, ○ : [Technical definition]: Process during which a cell and water (demineralization) which will be loses its mitotic activity and develops specialized released into the bloodstream structural elements and distinct functional properties due ↪ : Breakdown of inorganic portion to differential gene expression[Gilbert & Barresi Developmental Biology] ○ Lysosomal enzymes such as collagenase & 1. Starts from mesenchymal stem cells cathepsins[Harper’s p. 612] are also released to digest the ○ : Aka. Stromal stem cells, has the ability to self-renew collagen in the matrix, forming the Howship’s Lacunae (mitotic) and differentiate into osteoblasts, chondrocytes, : Breakdown of organic portion myocytes, and adipocytes Degradation products taken up by endocytosis are 2. Then differentiate into multipotent osteoblast transported across the cell in vesicles for secretion on the free ○ : Multipotent – capable of forming other types of cells surface ○ Mitotic activity decreased (and further decreases with further differentiation stages) ○ Possible alternative products: Fibroblast Chondrocyte Myocyte 3. Then differentiate into pre-osteoblasts ○ Multipotency decreased ○ Possible alternative product: Adipocytes 4. Then differentiate into osteoblast ○ Possible alternative product: Bone lining cell Figure 5. Osteoclast resorption mechanism 5. Then differentiate into osteocytic osteoblast ○ Not all osteoblasts becomes osteocytes. These are the Osteoclastogenesis osteoblasts that are then fated to become osteocytes 6. Then differentiate into osteocyte B. Osteocytes Embedded within the bone Derived from osteoblasts that get trapped in the lacunae Have long processes in contact with other osteocytes and lining cells Role: ○ Maintain extracellular calcium concentration Figure 6. Osteoclast differentiation process ○ Act as mechanoreceptors in the local activation of bone remodeling 1. Starts from Hematopoietic stem cells Mechanoreceptors: Stress or mechanical compression 2. Then differentiates into a multipotent progenitor to the bone are sensed by the osteocytes ○ In blood cell differentiation, this is the common myeloid progenitor C. Osteoclasts 3. Then differentiates into a monocyte Multinucleated giant cells derived from pluripotent ○ Also the precursor of macrophages hematopoietic stem cells (monocytes) 4-6. Then differentiate into pre-osteoclasts, mature osteoclast, ○ : M-CSF and RANK-L from the osteoblasts are and eventually Resorbing osteoclast responsible for osteoclast differentiation Undergoes apoptosis after bone resorption Page 3 of 13 | TH: MILLORA, I. | BCM TG 3 | ALCALA, ANGELES, GO, LIZARES, PULMONES, SY  BCM 1.06 Bone Biochemistry Proteins Involved in Osteoclastogenesis Balance between bone formation/deposition (mineralization) and resorption (demineralization) with no major changes in Macrophage Colony Stimulating Factor (M-CSF) bone mass or mechanical strength after each remodeling ○ Secreted by osteoblasts and helps in proliferation, cycle differentiation, and functional activation of monocytes ○ ↑ Ca in blood → Ca from the blood is transported inside ○ Binds to the receptor C-FMS (Colony Stimulating Factor the bones → Bone Deposition (mineralization) 1 Receptor) on monocytes ○ ↓ Ca in blood → Ca from the bones is transported outside Receptor Activator of Nuclear Factor-kappa B (RANK) to the blood → Bone Resorption (demineralization) ○ Receptor present in monocyte Phases of Bone Remodeling ○ TP Note: This is sometimes called Receptor Activator of Four distinct phases of bone remodeling NF-kB because NF-kB is a common intracellular protein ○ Distinct but they are overlapping with one another involved in immune cells RANK Ligand (RANKL) ○ Membrane-bound Ligand produced by osteoblasts ○ When the osteoblast is stimulated to produce RANKL, the ligand will bind to the RANK receptor in the monocyte allows the fusion of monocytes to form a multinucleated osteoclast cell Parathyroid Hormone (PTH) ○ Acts on osteoblasts by enhancing RANKL expression Osteoprotegerin (OPG) ○ Secreted by osteoblasts ○ Acts as a “decoy receptor” ○ Binds to RANKL, preventing it from binding to its receptor RANK : This is why OPG is a “decoy” because it acts as the receptor for the RANKL ligand ○ Prevents differentiation of monocyte into osteoclast to control bone resorption ○ OPG production is increased in the presence of estrogen TP Notes: : Not all ligands are free-floating compounds (Ex. acetylcholine). Some ligands can be attached to cell membranes (ex. RANKL) : “Eh yung RANK naka attach din sa cell membrane, paano malalaman alin ang receptor at alin ang ligand?” ○ The receptor is the one that will initiate downstream signaling ○ In simple terms, the receptor is on the side where cell activation occurs ○ In this case, the monocyte is activated to induce differentiation, making RANK (the protein present in monocytes) the receptor CLINICAL CORRELATIONS Clinical significance: Estrogen protects bone from extra Figure 7. Phases of Bone Remodeling (Fr Doc Visda’s Slides) resorption Table 1. Phases of Bone Remodeling Menopausal women that have lower estrogen have more fragile bones Phase I: Initiation/Activation of bone remodeling at a specific site. ○ OPG production is decreased and bone resorption rate Osteoclast precursors are recruited in the area of micro-cracks or is increased areas being remodeled. Women approaching menopause are advised to exercise Osteoblasts are activated and produce RANKL & M-CSF to preserve the bone ○ RANKL binds to RANK receptors , while M-CSF binds to C-FMS → Enhances Osteoclast Differentiation/Maturation Phase II: Bone Resorption and concurrent recruitment of III. BONE REMODELING mesenchymal stem cells (MSCs) and osteoprogenitors Bone is in constant remodeling, and it is essential for bone Mature Osteoclast secretes acids & enzymes for bone resorption. strength Osteoclasts produce a pit called Howship’s lacunae after the ○ Allows bone to adapt to both physical and hormonal digestion of collagens and hydroxyapatite. Batch 2028 signals Batch 2028 Also, mesenchymal stem cells (MSCs) and progenitor cells are ○ Reshape bones after a fracture or to repair micro-cracks recruited in the Howship’s lacunae when a bone undergoes stress Batch 2028 ○ Early osteoblast differentiation is initiated Page 4 of 13 | TH: MILLORA, I. | BCM TG 3 | ALCALA, ANGELES, GO, LIZARES, PULMONES, SY  BCM 1.06 Bone Biochemistry Phase III: Osteoblast differentiation and function (osteoid Typical Manifestation synthesis) ○ Early stage: almost no visible manifestation Osteoid synthesis from osteoblasts begin to overtake over. Bone ○ Loss of height over time resorption decreases Feng & McDonald (2011) ○ Increased risk of fracture Osteoblast secretes matrix mainly composed of collagen ○ Back pain (organic; osteoid seam) ○ Hunched posture Phase IV: Mineralization of osteoid and completion of bone remodeling Mineralization of Osteoid ○ Calcium and phosphate deposit on the osteoid seam, forming hydroxyapatite to give bones strength that it needs (inorganic) A. Factors Affecting Bone Remodeling Batch 2028 Mechanical Stress ○ Wolff’s Law Figure 9. Progression of Vertebral Alignment : ↑ weight applied on bone : ↑ rate of remodeling Hormones Prevention ○ Parathyroid hormone (PTH) ○ Workout (boosts bone health) From the parathyroid gland ○ Eat high Ca and Vit D foods Activated when plasma Ca2+ is low ○ Vitamins and Supplements PTH stimulates osteoblasts → increase RANKL → ○ Avoid smoking and drinking RANKL triggers bone resorption → calcium ions are released into the bloodstream Two Types of Osteoporosis Batch 2028 : ↓ Blood calcium levels : ↑ PTH ○ Calcitonin 1. Primary Osteoporosis can be caused by physiologic From the parafollicular cells in the thyroid gland processes such as menopause or aging Activated in the presence of high plasma ○ Menopause-associated (type 1) [Harper’s, 614] concentration of Ca2+ Common causes of osteoporosis are often linked to : ↑ Calcitonin : ↓ Bone resorption menopause Vitamin D ○ Age-related (Type 2 or senile osteoporosis)[Harper’s, 614] ○ Stimulates intestinal calcium absorption → increases occurs in both sexes (>75yo) plasma calcium ion concentration more prevalent in women 2:1 ratio Vitamin D Deficiency can lead to hypocalcemia due 2. Secondary Osteoporosis can be a result of taking to decreased Ca2+ absorption glucocorticoids or as a result of chronic immobilization Batch 2028 ○ PTH hormone is necessary for Vit D activation Guyton 14th ed. p1002 ○ Glucocorticoid-induced : Low plasma Ca2+ concentrations = activate PTH ○ Immobilization-induced = Vit D Activation Pathophysiology IV. Bone Conditions A. Osteoporosis Figure 8. (L) Healthy Bone Matrix (R) Osteoporotic Bone Matrix Occurs when bone resorption is much higher than deposition The normal bony matrix should appear like soap or honeycomb (Left of Fig 9) if they lose their density they are easily broken In osteoporosis, the honeycomb appearance of bone disappears and a more porous appearance predominates ○ More porous appearance is indicative of more bone resorption. Figure 10: Pathophysiology of Osteoporosis ○ common condition that both affects males and females Risk Factors Women entering menopause or in menopausal stage have ○ Gender: female lower estrogen levels The Estrogen is lost : General rule: Estrogen inhibits osteoclastogenesis ○ Advanced age ○ = less osteoclasts = less resorption ○ Asian-American race (genetic) Lower estrogen leads to loss of inhibitory signal, promoting Can be due to diet since we lack Ca or Vit D in our diet osteoclast differentiation leading to enhanced resorption. This ○ Small body frame leads to more bone being broken down than being made. Page 5 of 13 | TH: MILLORA, I. | BCM TG 3 | ALCALA, ANGELES, GO, LIZARES, PULMONES, SY  BCM 1.06 Bone Biochemistry Bisphosphonates (“-dronate e.g. Alendronate) (Gathered from Doc Visda when we asked her after lecture) ○ Synthetic compounds that can bind to hydroxyapatite IL1, IL6, and TNF are proinflammatory cytokines crystals found in bone ○ Cytokines - signaling molecules of immune cells. You can This effectively retards the rate of demineralization think of this as the special hormones of the immune and bone loss system SERMs (Selective Estrogen Receptor Modulators) ○ Proinflammatory because they function during ○ This drug selectively binds to estrogen receptors and inflammation (Ex. rashes, insect bite, physical trauma) perform the functions of estrogen (e.g. Raloxifen) ○ Because they function in the activation of osteoclast Selective binding occurs in estrogen receptors precursors, bone remodeling can actually speed up involved in the osteoclastic differentiation, thus, during fractures because the fracture area attract protective of bone proinflammatory cytokines to the damaged area Table 2. Discoveries on Pathophysiology of Osteoporosis YEAR DISCOVERY 1980s Estrogen can block the release of monocytes and cells of osteoblastic lineage from producing IL-1 and TNF TNF and IL-1 are cytokines that play a role in osteoclast precursor and osteoclast differentiation Menopausal women ↓ estrogen = ↑osteoclast differentiation which affects bone overtime 1990s Osteoprotegerin (OPG) is a soluble decoy OPG binds to RANKL, preventing RANKL from Figure 11. radiograph of the Lumbar vertebrae on Healthy (A) and binding to RANK Osteoporotic patient (B) ○ No osteoclast precursor differentiation Absence of estrogen = OPG declines = ↑ RANKL - Comparing the two plates from Fig 11, there are visible RANK binding = uncontrolled production of irregular shape and micro fractures in plate B due to osteoclasts = ↑ bone resorption ↑osteoclast activity Early Role of T cells in osteoclast differentiation ○ Can cause compression of spine resulting to kyphotic 2000s T cells produce TNF posture ○ TNF stimulates osteoclastogenesis Absence of estrogen = uncontrolled differentiation B. Rickets of osteoclasts from TNF activation Childhood disease that affects bone development in children. 2006 FSH stimulates activation of osteoclast precursors : Metabolic abnormality: Vit D deficiency In menopause ↓ estrogen = ↑FSH secretion of the It causes: pituitary gland (a negative feedback) = ○ bone pain ↑differentiation of osteoclast precursor to ○ poor growth osteoclasts ○ soft weak bones that can lead to bone deformities. 2007 Estrogen promotes osteoclast apoptosis ○ bowing of bones or bow-leggedness (most common In menopause ↓ estrogen = decreased rate of presentation) osteoclast apoptosis (death) Summary: In women of Menopausal age: ↓ estrogen ↓OPG ↑FSH ↑TNF = ↑osteoclast differentiation = ↑bone resorption In patients of menopausal age, Estrogen and FSH levels can be used to confirm menopause. ○ It should be: ↓ estrogen ↑FSH Management Lifestyle Modification Figure 14. Bowing of lower extremities in radiograph ○ Proper Diet and Nutrition ○ Physical Activity Adults can experience a similar condition called ○ Avoid Smoking or drinking Osteomalacia or soft bones Estrogen Replacement Primary ○ Synthetic form ○ The mechanism of action is the decreased synthesis of ○ Administered orally or via ingestion vitamin D which most often is a result of: Calcium and Vitamin D ○ lack of exposure to sunlight ○ Important in the management of osteoporosis ○ lack of supplementation in breastfeeding infants. ○ To maintain normal levels of calcium in the blood Secondary Low levels of calcium in the blood can stimulate PTH ○ Can result from: secretion which further aggravates osteoclastic Malabsorption (intestinal malabsorptive states) activity or bone resorption Severe liver disease Vitamin D improves absorption of calcium in the Impaired renal function intestines Heritable abnormalities in Vitamin D metabolism Page 6 of 13 | TH: MILLORA, I. | BCM TG 3 | ALCALA, ANGELES, GO, LIZARES, PULMONES, SY  BCM 1.06 Bone Biochemistry C. Renal Osteodystrophy Heterogeneous group of bone diseases that accompany kidney disease (chronic kidney disease or end-stage renal disease) : In kidney diseases, there will be dysregulated calcium, phosphate and Vitamin D homeostasis ○ Hyperphosphatemia - high blood phosphate levels ○ Hypocalcemia - low calcium levels in the blood Triggers the constant release of PTH leading to Figure 15. Normal bones (L) vs Bone w/ Rickets (R) secondary hyperparathyroidism National Kidney Foundation (2024) (refer to pathophysio of rickets for full explanation) Pathophysiology ○ Abnormal PTH regulation due to ↓Ca Vitamin D deficiency caused by malnutrition or ↓ exposure to ○ Vit D deficiency sunlight can result in the development of secondary parathyroidism. Pathophysiology ○ Without Vit D, the intestinal absorption of Calcium decreases triggering the parathyroid gland to release more PTH Recall of PTH Action PTH increases bone resorption (demineralization) in an attempt to increase calcium levels in the blood As a consequence, the minerals in the bone decrease, softening and weakening the bones. Figure 17. Recall of PTH Action In ↓ Calcium levels → Parathyroid secretes PTH Actions of PTH: ○ In the Bone: ↑ Osteoclast Activity → ↑ bone Resorption =↑ Ca in blood (hypercalcemia) ○ In the kidneys: ↑ Ca Reabsorption → hypercalcemia Metabolism of Vit D and Calcium Figure 16. Summary of Pathophysiology of Rickets Management Vitamin D deficiency treatment ○ ↑Sun exposure ○ Dietary supplements ○ Proper nutrition For breastfed infants, Vit D and Ca can be given to mothers Page 7 of 13 | TH: MILLORA, I. | BCM TG 3 | ALCALA, ANGELES, GO, LIZARES, PULMONES, SY  BCM 1.06 Bone Biochemistry Pathophysiology Figure 18. Activation Pathway of Vit D Vitamin D Crucial in the absorption of calcium in the intestines. ○ : ↓ vitamin D = ↓ absorption of Ca2+ in the intestines ○ Resulting in low blood calcium levels which stimulate the release of parathyroid hormones → ↑osteoclast Figure 12: Osteoclast in an area of resorption (resorption lacunae) activity → ↑ bone resorption. Vit D activation pathway Defective function of several genes affecting bone resorption ○ Step 0 (Skin): we have 7-dehydrocholesterol which Bone resorption in osteoclasts: Batch 2028 came from reabsorbed cholesterol in the intestines ○ Osteoclast: has a ruffled border, where active exchange ○ Step 1 (Skin): Upon UV exposure, this is converted of the ions responsible for resorption occurs, in the into Cholecalciferol (Vit D3) and transported to the resorption lacunae. liver ○ Hydrogen and chloride ions: responsible for the ○ Step 3 (Liver): Cholecalciferol (Vit D3) is dissolution of bone matrix in bone resorption. hydroxylated to 25-hydroxycholecalciferol One of the genetic causes of osteopetrosis is due to the (Calcifediol) mutations in the gene (loc. in chromosome 8q22) which ○ Step 4 (Kidney): 25-hydroxycholecalciferol encodes for carbonic anhydrase II (CA II) [Harper’s, 614] (Calcifediol) is hydroxylated to ○ CA II deficiency → inhibition of normal bone resorption 1,25-dihydroxycholecalciferol (Calcitriol) → osteopetrosis the active form of Vit D Requires PTHGuyton H+ AND Cl- IONS IN BONE RESORPTION (see fig 12): Batch 2028 Kidney plays a vital role in activating Vit D hence, in 1. Chloride ions (Cl-): sourced through the patients with chronic kidney disease not able to produce chloride ion - bicarbonate exchanger the active form of vitamin D (Calcitriol or 1,25- 2. Chloride is transported from the cell apex to the ruffled border dihydroxycalciferol) = ↓ calcium absorption where chloride ion channels (CLCN7) are found. 3. This results in the transport of chloride ions out of the cell into Clinical Presentation the resorption lacunae. 4. Hydrogen ions (H+): produced from the catalytic action of carbonic anhydrase (CAII) as summarized in the following chemical reaction: a. Carbonic anhydrase catalyzes the reaction between CO2 and H2O to produce carbonic acid (H2CO3) b. H2CO3 dissociates into hydrogen ion and bicarbonate Figure 19. Lytic bone lesions in CKD patients 5. Hydrogen ion is pumped out of the osteoclast through the V- As seen in the radiograph in Figure #, there are areas with ATPase pump lytic bone lesions. 6. Bicarbonate exits the cell through the chloride-bicarbonate ○ Lytic bone lesions: areas where bone has been exchanger destroyed, leaving a hole or cavity This action of the hydrochloric acid (HCl) on the bone matrix is In CKD patients, therefore, administration of oral calcium responsible for the following: and vitamin D is necessary to maintain normal levels of ○ Dissolution of the bone calcium in the blood, preventing bone loss from secondary ○ Release of calcium ions parathyroidism Carbonic Anhydrase II is one of four isozymes of carbonic anhydrase present in human tissues. It is the same enzyme responsible for the D. Osteopetrosis activity of the Bicarbonate buffer. If a bone resorption problem is Marble Bone Disease[Harper’s, 614] caused by CA II deficiency, this would also affect the body’s regulation Group of rare, heritable bone remodeling disorders of acids thru the bicarbonate buffer resulting in abnormal accumulation Characterized by increased bone density caused by inhibition of acid in the body including the kidneys. The condition is now called of bone resorption in osteoclasts Osteopetrosis with Renal Tubular Acidosis or Guibaud-Vainsel ○ : Osteoblastic activity (Bone mineralization) >> syndrome. National Organization for Rare Disorders 2024 Osteoclastic activity (Bone Resorption) Page 8 of 13 | TH: MILLORA, I. | BCM TG 3 | ALCALA, ANGELES, GO, LIZARES, PULMONES, SY  BCM 1.06 Bone Biochemistry Genetic Causes Table 4. Mild vs Severe Osteogenesis Imperfecta Osteopetrosis can have a lot of genetic causes Mild Severe ○ Results in a dysfunction in the process of bone resorptive Fractures during Occurrence of activities of the osteoclast Childhood and Fractures before birth fracture adulthood Table 3. Genetic causes of Osteopetrosis Genetic Disease Blue or grey tint Subtype Gene Function Frequency Severity Eye Blue sclerae to the part of Somewhat more Autosomal Produces H+ in