BONE ANATOMY Daniel D Bikle, MD, PhD Professor of Medicine, UCSF 1 - - PowerPoint PPT Presentation

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Mar 18, 2023 36 likes •117 views

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

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Basics of Bone Biology

Daniel D Bikle, MD, PhD Professor of Medicine, UCSF

BONE ANATOMY

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Origin of Bone Cells

Osteoblast / stromal cells

1a.25(OH)2D3, PTH, IL-11

M-CSF

C-Fms

Osteoclast progenitors

RANK RANKL RANKL

OPG OPG

RANKL

Perfusion osteoclasts (pOCs) Osteoclasts Activated osteoclasts

Proliferation & Differentiation Survival & Fusion

RANK

Activation

Osteocytes Osteoclasts

Reversal

Apoptotic Osteoclasts Lining Cells Osteocytes

Activation

Osteocytes

Formation

Osteoblasts Osteocytes

Resorption Resting Phase

Osteoclasts Osteoclasts

Bone Remodeling

Osteoid Lining Cells Osteocytes Preosteoblasts

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Osteoclasts resorbing bone Osteoblasts lining bone over resorption cavity Remodeling fails with age leading to osteoporosis

Hormonal Regulation of Bone Growth and Remodeling

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PTHrP, IHH, and IGF

Paracrine regulators of growth plate development

Strewler, NEJM 342:177, 2000

IGF1 regulation of PTHrP

Resting Chondrocyte Proliferating Chondrocyte Hypertrophic Chondrocyte Prehypertrophic Chondrocyte

+

IGF1

+

Ihh PTHrP

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PTH, FGF23, and IGF

Endocrine regulators of bone remodeling

Human Parathyroid Hormone 1-34 and 1-84

1 10 20 30 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His Asn Phe 50 40 60 70 80

COOH

H2N-

Niall HD et al. Proc Natl Acad Sci USA 1974;71:384-388

Intact PTH is hPTH (1-84) Teriparatide is hPTH (1-34)

synthetic
recombinant

PTH/PTHrP Receptor Activation

Cyclic AMP DAG, IP3 Cai

C PTH N

From Jüeppner et al. in Endocrinology, Eds. DeGroot & Jameson, 2001

Extracellular Intracellular

Classical Actions of PTH

PTH PTH Release Ca and Pi from bone Reabsorb Ca in distal tubules, decrease Pi absorption in proximal tubules Synthesis of 1,25 (0H)2 D3 Absorb Ca and Pi In Small Intestine

Maintain Serum Ca and Pi Levels

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FGF23

The new kid on the block and the long sought phosphatonin

Fukumoto and Yamashita, Bone 40:1190-95, 2007 Fukumoto and Yamashita, Bone 40:1190-95, 2007

IGF1 and IGF2

Regulators of both bone formation and resorption: required for PTH action

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IGF1 REGULATED SKELETAL GROWTH:

IGF1 NULL MOUSE

Denley et al Cytokine and Growth Factor Reviews 16:421-439, 2005

IGF signaling pathway

Bikle et al JBMR 17:1570,2002

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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
steocytes 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

f growth and remodeling