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The Fascinating Living Skeleton
Neveen A.T. Hamdy
Department of Medicine, Division of Endocrinology
& Centre for Bone Quality
Leiden University Medical Center , The Netherlands
Neveen A.T. Hamdy has no Disclosures
relevant to this Talk
Bone: A Dynamic Multifunctional Organ
Functions
• Mechanical
• Protective for vital organs
• Metabolic:
• Reservoir for minerals
• Bone remodeling
Bone is a unique tissue
Complex tissue
• Cells
• Organic matrix
• Mineral
Continuously renewed tissue
A normal bone remodeling cycle is essential
for the maintenance of bone mass and quality
Seeman E and Delmas PD. N Engl J Med 2006; 354:2250–2261
Mineralisation
- calcium
- phosphate
- vitamin D
Bone Mineralization
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Mw. Dr. N
.A.T. H
amdy
Bone Remodeling
The Basic Multicellular Unit (BMU) Bone Cells: The Osteoclast
Tolar et al, N Engl J Med 2004;351:2839-2849
Specific Factors Are Needed for the
Maturation of Haematopoietic Stem CellsHaematopoietic
Stem Cell
Myeloid
ProgenitorLymphoid
Progenitor
Monocyte
Progenitor
Osteoclasts
Erythrocytes
EPO
M-CSF1
SCF
RANK LigandLymphoid
Cells
Granulocytes
GM-CSF
SCF
M-CSF1
Macrophages
EPO, erythropoietin; GM-CSF, granulocyte macrophage colonies stimulating factor; M-CSF1, macrophage CSF; SCF, stem cell factor
RANK Ligand
Activated
Osteoclast
Bone
Pre-fusion
OsteoclastRANK
CFU-M
Multinucleated
Osteoclast
Activation
Growth factors
Hormones
Cytokines
Role of RANK Ligand in Osteoclastogenesis
Adapted from Boyle WJ et al. Nature 2003; 423: 337–342 (Courtesy AMGEN)
Differentiation
Survival
RANK
RANK Ligand
OPG
Role of Osteoprotegerin (OPG) in controlling
osteoclastogenesis
Osteoclast Formation, Function and
Survival Inhibited by OPG
Growth Factors
Hormones
Cytokines
Mature
Osteoclast
CFU-M
Pre-fusion
Osteoclast
Multinucleated
Osteoclast
Bone
Adapted from Boyle WJ et al. Nature 2003; 423: 337–342 (Courtesy AMGEN)
Normal bone remodeling cycle
Seeman E, Delmas PD. N Engl J Med 2006
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Mw. Dr. N
.A.T. H
amdy
Regulation of Osteoblast development
and Survival
Sclerosteosis/van Buchem’s Disease
Bo
ne
thic
kn
ess
Normal
Bone remodeling time
Sclerostin
-
Van Bezooijen et al 2004 J Exp Med
Osteocyte-derived sclerostin is a negative
modulator of bone formation
osteocytes
Normal bone remodeling = Healthy skeleton A normal bone remodeling cycle is essential
for the maintenance of bone mass and quality
Seeman E and Delmas PD. N Engl J Med 2006; 354:2250–2261
Me
tab
oli
c B
on
e D
ise
ase
s?
Dysfunctional Cells
Oc Ob
Imbalanced remodelingHigh Bone turnover Dysfunctional Osteoclasts
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Mw. Dr. N
.A.T. H
amdy
In bone marrow cultures from pagetic bone
• osteoclasts
– form more rapidly
– produce increased levels of IL-6
– express increased levels of IL-6 receptors
• Increased expression of RANK-ligand
Paget’s Disease of Bone
Genetic predisposition
Osteopetrosis
Before and after Bone marrow
Transplantation
Dysfunctional osteoblasts
Pathogenesis of Fibrous Dysplasia
Fibrous DysplasiaClinical Spectrum of Fibrous Dysplasia
McCune-Albright Syndrome
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.A.T. H
amdy
Apoptosis of osteoblasts and osteocytes
Weinstein, J. Clin. Invest. 1998
Pathophysiology of glucocorticoid-induced bone loss
OPG Production in Human Ob Lineage Cells
Hofbauer, Endocrinology 1999Manolagas & Weinstein JBMR 1999
Aluminium Bone Disease
Adynamic Bone Disease
Also as a result of:
- Alcohol intoxication
- Haemochromatosis
Osteoblast Toxicity
Abnormal Collagen Synthesis- Osteogenesis Imperfecta -
Defective mineralisation
Vitamin D deficiency and defective
mineralization of the skeleton
Rickets
Osteomalacia
Severe “Renal
Rickets”(HPTP + OM)
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.A.T. H
amdy
FGF-23
25(OH)D
Osteoporosis
PTH
Disturbed Bone & Mineral Homeostasis in CKDVitamin D deficiency and disturbed bone & mineral
homeostasis in CKDHypophosphatemic Rickets
(Mutation in the PHEX gene)
Looser zone
Sclerosteosis/van Buchem’s Disease
Bo
ne
thic
kn
ess
Normal
Bone remodeling time
Sclerostin
-
Van Bezooijen et al 2004 J Exp Med
Osteocyte-derived sclerostin is a negative
modulator of bone formation
osteocytes
First Case (1955)
van Buchem’s DiseaseUrk
(n=20)
52-kb deletion 35 kb downstream of SOST gene
(strictly affects bone formation)
Balemans et al. 2001, 2002, 2005; Brunkow 2001; Staehling-Hampton et al. 2002
van Buchem’s disease
SclerosteosisMutations of SOST gene (5 so far)(affects bone formation + digit development)
The SOST gene and sclerosing bone dysplasias Sclerosteosis / van Buchem’s Disease
1
1
2
Van Bezooijen et al 2004 J Exp Med
Sclerosteosis Van Buchem’s
No sclerostin expression
Normal Bone
Sclerostin expression by osteocytes Low sclerostin expression
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Mw. Dr. N
.A.T. H
amdy
Sterno-costo-clavicular Hyperostosis
Increased Bone Turnover
Hyperparathyroid Bone Disease
Pre-PTx 6m post-PTx
Imbalance in Bone
Remodeling
Normal bone
Skeletal disorder characterized by compromised bone strength
predisposing to an increased risk of fracture. Bone
strength reflects the integration of two main features:
bone mass and bone quality
Osteoporosis
NIH Consensus Development Conference: 2000
Osteoporosis
Osteolytic bone lesions in malignancy
Breast Carcinoma Multiple Myeloma
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.A.T. H
amdy
Osteoblastic
Metastases in Prostate Cancer
Osteolytic
Androgen deprivation
A normal bone remodeling cycle is essential
for the maintenance of bone mass and quality
Seeman E and Delmas PD. N Engl J Med 2006; 354:2250–2261
Me
tab
oli
cB
on
eD
ise
ase
s?
“ In many instances, nature has arranged an
experiment in a sick individual and partly
completed it; all that is needed are the eyes of
the clinician to make certain observations, and
the background of the investigator to plan other
observations and interpret them.”
Fuller Albright, 1944
Therapeutic potential of
modulating bone remodeling
Disorders of Bone
Remodeling
?
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.A.T. H
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