7/11/2019 Basics of Bone Biology BONE ANATOMY Daniel D Bikle, MD, PhD Professor of Medicine, UCSF 1
7/11/2019 Origin of Bone Cells Bone Remodeling Proliferation M-CSF & Differentiation C-Fms Resting Phase Activation Osteoclast Perfusion osteoclasts progenitors (pOCs) RANK OPG Lining Cells Lining Cells RANKL Osteoclasts Survival & Fusion RANKL Osteoblast / stromal cells Osteocytes Osteocytes RANK 1 a .25(OH) 2 D 3 , PTH, IL-11 Resorption Reversal Formation RANKL OPG Osteoclasts Apoptotic Osteoclasts Osteoclasts Osteoblasts Osteoclasts Activation Preosteoblasts Osteoid Osteocytes Osteocytes Osteocytes Activated osteoclasts 2
7/11/2019 Osteoclasts resorbing bone Osteoblasts lining bone over resorption cavity Remodeling fails with age leading to osteoporosis Hormonal Regulation of Bone Growth and Remodeling 3
7/11/2019 PTHrP, IHH, and IGF Paracrine regulators of growth plate development IGF1 regulation of PTHrP Resting Chondrocyte + PTHrP Proliferating Chondrocyte - IGF1 + Ihh Prehypertrophic Chondrocyte Hypertrophic Chondrocyte Strewler, NEJM 342:177, 2000 4
7/11/2019 Human Parathyroid Hormone 1-34 and 1-84 1 10 H 2 N- Teriparatide is Ser Val Ser Glu Ile Gln Leu Met His Asn Leu hPTH (1-34) 20 Gly His Lys Ser Leu Glu Val Arg Glu Met Asn - synthetic PTH, FGF23, and IGF Trp - recombinant Leu Val Asn Arg Lys Lys Leu Gln Asp His Phe 30 Intact PTH is Endocrine regulators of bone remodeling 40 hPTH (1-84) 50 60 70 80 - COOH Niall HD et al. Proc Natl Acad Sci USA 1974;71:384-388 PTH/PTHrP Receptor Activation Classical Actions of PTH C N PTH PTH Absorb Ca and Pi In Small Intestine PTH Extracellular Release Ca Reabsorb and Pi from Synthesis of Intracellular Ca in distal bone 1,25 (0H) 2 D 3 tubules, decrease Pi absorption in proximal tubules Ca i ++ Cyclic AMP DAG, IP 3 Maintain Serum Ca and Pi Levels From Jüeppner et al. in Endocrinology, Eds. DeGroot & Jameson, 2001 5
7/11/2019 FGF23 The new kid on the block and the long sought phosphatonin Fukumoto and Yamashita, Bone 40:1190-95, 2007 IGF1 and IGF2 Regulators of both bone formation and resorption: required for PTH action Fukumoto and Yamashita, Bone 40:1190-95, 2007 6
7/11/2019 IGF1 REGULATED SKELETAL GROWTH: Denley et al Cytokine and Growth Factor Reviews 16:421-439, 2005 IGF1 NULL MOUSE IGF signaling pathway Bikle et al JBMR 17:1570,2002 7
7/11/2019 THE KEY ROLE OF EPHRINS Bidirectional signaling molecules regulated by IGF1 but required for IGF1 and PTH action on bone Mundy GR and Elefterious F Cell 126:441, 2006 SUMMARY • Bone is a dynamic tissue • Chondrocytes, osteoblasts, osteoclasts, and osteocytes are the principal cells responsible for bone growth and remodeling • Chondrocytes form the cartilage, osteoblasts form bone, osteoclasts resorb bone, osteocytes sense stress and control remodeling • IGF, IHH and PTHrP are the key paracrine factors regulating growth • IGF, PTH, FGF23 are the key endocrine factors regulating bone remodeling • Cell-cell communication by RANKL/RANK and EphrinB2/EphB4 are critical for hormonal regulation of growth and remodeling 8
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