Skeletal Physiology & Pharmacology Part 2

#14 Skeletal Physiology & Pharmacology Part 2 of 4 J O N AT H A N L O W E R Y, P H D A S S I S TA N T P R O V O S T F O R R E S E A R C H & S C H O L A R S H I P A S S O C I AT E P R O F E S S O R O F P H Y S I O L O G Y...

#14 Skeletal Physiology & Pharmacology Part 2 of 4 J O N AT H A N L O W E R Y, P H D A S S I S TA N T P R O V O S T F O R R E S E A R C H & S C H O L A R S H I P A S S O C I AT E P R O F E S S O R O F P H Y S I O L O G Y [email protected] V I R T U A L O F F I C E H O U R S T H U R S D AY S 9 : 3 0 – 1 0 : 3 0 A M ( J L O W E R Y )  Learning Objectives for Lectures 13 - 16 1. Identify the four major bone cell types and describe the lineage and markers (if discussed) for each. 2. Discuss the process of bone remodeling, detailing the function of osteocytes, bone lining cells, osteoclasts, and osteoblasts in this process. 3. Describe the net impact of changes in bone formation rate and/or bone resorption rate on bone mass and relate serum/urinary bone turnover markers to bone formation and resorption. 4. Describe the role of Sclerostin in osteocyte-dependent regulation of osteoblast activity and be able to identify the hallmarks of decreased Sclerostin expression or activity. 5. Discuss the impact of Growth Hormone on bone formation and be able to identify the hallmarks of elevated Growth Hormone expression. 6. Discuss how osteoblasts regulate osteoclastogenesis and how PTH impacts this process. 7. Relate how changes in the differentiation rate of osteoclasts may alter bone resorption rate. 8. Describe what osteoporosis is and its underlying pathophysiology. 9. Describe how osteoporosis is diagnosed, how it is evaluated, and its consequences. 10. List and apply the NOF guidelines when to initiate pharmacotherapy for osteoporosis. 11. Name the major FDA approved drugs (only the ones discussed) used for treating osteoporosis, identifying the mechanism of action of each. 12. List and apply the AACE guidelines on first line drugs for treating osteoporosis.  Concept Map for Lectures 13-16  Central Theme: Defects in bone material properties and/or cellular function underlie metabolic disease of bone.  Lecture 13: Matrix properties and bone formation  Lecture 14: Bone remodeling  Lecture 15: Osteoporosis diagnosis and pharmacology  Lecture 16: Osteoporosis pharmacology Key principles of bone remodeling 1. Specific cell types perform specific roles. 2. Bone volume increases on surfaces. 3. Bone matrix remodeling occurs continually. 4. Bone mathematics: Bone mass = formation rate – resorption rate. 5. Bone matrix remodeling is coupled. Key principles of bone remodeling 1. Specific cell types perform specific roles. 2. Bone volume increases on surfaces. 3. Bone matrix remodeling occurs continually. 4. Bone mathematics: Bone mass = formation rate – resorption rate. 5. Bone matrix remodeling is coupled. Key principles of bone remodeling 1. Specific cell types perform specific roles. 2. Bone volume increases on surfaces. 3. Bone matrix remodeling occurs continually. 4. Bone mathematics: Bone mass = formation rate – resorption rate. 5. Bone matrix remodeling is coupled.  Spongy (trabecular, cancellous) bone Trabeculae Spongy bone Cortical bone Images adapted from http://health.tipsdiscover.com, ClydeNET, and Junquiera’s Basic Histology  Compact (cortical, lamellar) bone (osteon) Adapted from the UCSD Histology Image Bank Lippincott’s Illustrated Reviews: Physiology Compact (cortical, lamellar) bone Birefringence due to alternating pattern of collagen fibers Compact (cortical, lamellar) bone The majority of microcracks occur in interstitial lamellae and terminate at osteon boundaries. Key principles of bone remodeling 1. Specific cell types perform specific roles. 2. Bone volume increases on surfaces. 3. Bone matrix remodeling occurs continually. 4. Bone mathematics: Bone mass = formation rate – resorption rate. 5. Bone matrix remodeling is coupled. The process of bone matrix remodeling Lippincott’s Illustrated Reviews: Physiology  LO #2, 3 Serum markers of bone turnover Collagen I fragments (CTx) Collagen I propeptide (P1NP) Lippincott’s Illustrated Reviews: Physiology Key principles of bone remodeling 1. Specific cell types perform specific roles. 2. Bone volume increases on surfaces. 3. Bone matrix remodeling occurs continually. 4. Bone mathematics: Bone mass = formation rate – resorption rate. 5. Bone matrix remodeling is coupled.  Bone math Balanced Osteoblast and osteoclast activity are coupled.  Bone math Bone mass accrual May be due to: increased osteoblast activity, decreased osteoclast activity, or both  LO #2, 3, 4 Bone math Bone mass loss May be due to: decreased osteoblast activity, increased osteoclast activity, or both  Osteoclasts Multinucleated Monocyte/Macrophage Osteoclast osteoclast lineage cell precursor Activated Carbonic anhydrase osteoclast Cathepsin K RANK Receptor Adapted from Del Fattore et al 2012  Osteoclasts Osteoclasts secrete proteases and acid on the bone surface, thereby degrading the matrix. Defects in osteoclastogenesis and/or function underlie osteopetrosis, which is characterized by dense bones that are prone to fracture. High bone mass does not always reduce fracture risk. Adapted from Del Fattore et al 2012  Osteoclasts Osteoclastogenesis is regulated by the actions of RANKL and OPG RANK Receptor OPG Both are produced by osteoblasts OPG RANKL What if the ratio could be shifted pharmacologically… teaser for osteoporosis management!  Clinical Application 1: Post-menopausal osteoporosis Estrogens are potent inducers of osteoclast apoptosis and also reduce RANKL- RANK Receptor OPG dependent differentiation OPG RANKL Gonadal production of estrogen levels is low in post-menopausal women… Does this lead to increased or decreased bone resorption?  Clinical Application 2: Hyperparathyroidism Parathyroid hormone (PTH) signaling increases RANKL expression and decreases OPG expression RANK Receptor OPG OPG Does this lead to increased or decreased RANKL osteoclastogenesis? PTH levels are abnormally high in primary hyperparathyroidism, which leads to hypercalcemia and bone loss due to increased osteoclastogenesis  Summary of bone cell types and functions Osteoblast Osteocyte Osteoclast “Bob the Blast” “Sally the Cyte” “Carl the Clast” Mechanosensor, Mineral Major Function Secrete bone matrix Degrade bone matrix homeostasis Osteoprogenitor → Lineage Osteoprogenitor Monocyte/Macrophage Osteoblast Romosozumab targets an Targeted by drug Teriparatide, Bisphosphonates, osteocyte-derived Abaloparatide Denosumab protein Images copyright John Wiley & Sons, used with permission