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Mechanisms in chronic kidney disease Mechanisms of CKD-MBD: New insights in the pathogenesis Jorge Cannata-Andia University of Oviedo Oviedo, Spain Mechanisms of CKD-MBD: New Insights in the Pathogenesis Role of Classic and New Players in

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SLIDE 1

Mechanisms of CKD-MBD: New insights in the pathogenesis

Mechanisms in chronic kidney disease

Jorge Cannata-Andia University of Oviedo Oviedo, Spain

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SLIDE 2
  • Role of Classic and New Players in the Pathogenesis
  • f Secondary Hyperparathyroidism and CKD-MB

Role of * Calcium (Calcimimetics) * Vitamin D Receptor Activators (VDRAs) * Phosphorus and FGF 23

Mechanisms of CKD-MBD: New Insights in the Pathogenesis

* Phosphorus and FGF 23 * Genomic & Molecular Changes in the Severe and Refractory Secondary Hyperparathyroidism

  • The Links Between the Bone and Vascular Axis in CKD-MBD.

Role of Phosphate in the Pathogenesis of Vascular Mineralization and Bone Demineralization. Possible Self-defensive Mechanisms Triggered by the Vascular System

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SLIDE 3

MEDICINE 22: 103-161; 1943

1943: Renal Osteodystrophy (RO) (Liu et al, Medicine)

  • Secondary Hyperparathyroidism
  • Osteomalacia
  • Osteosclerosis
  • Osteoporosis

Mechanisms of CKD-MBD: New Insights in the Pathogenesis

1970’s – 1980’s: PTH Assays and Bone Biopsy Diagnosis of ROD Useful in Clinical Practice (1980´s – 2007) 30 Following Years: Academic Concept With No Chance to be Applied in the Daily Clinical Management of CKD Patients

In 2006 a New Term was Proposed with a Broader Scope

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SLIDE 4

Kidney Disease Improving Global Outcomes

Mechanisms of CKD-MBD: New Insights in the Pathogenesis

Renal Osteodystrophy

Secondary Hyperparathyroidism the Vessels & Bone Play Important Role

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SLIDE 5

PTH FGF23/Klotho

  • Aluminium
  • Estrógenos
  • Magnesio
  • Acidosis
  • Otros……

Parathyroid Regulation in Chronic Kidney Disease Calcitriol

Phosphorus 25(OH)D

Cannata –Andía JBy Rodriguez M.. Nefrología Clínica . Ed L Hernando, 2008,

FGF23/Klotho

Calcium

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SLIDE 6

PTH FGF23/Klotho

Parathyroid Regulation in Chronic Kidney Disease

CaSR

CaSR Discover and Cloned in 1993 G Protein-Coupled Receptor (GPCR) Cell Surface Receptor Able to Recognize and Respond to Extracellular Calcium and Others: Al, La, Sr, Ga, .......

Calcitriol

Phosphorus

Cannata –Andía JBy Rodriguez M.. Nefrología Clínica . Ed L Hernando, 2008,

FGF23/Klotho

Calcium

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SLIDE 7

Parathyroids

Tissue Distribution Parathyroid and C cells Renal proximal tubule Nephron segments Gastrointestinal tract

Calcium Sensing Receptor (CaSR)

Gastrointestinal tract Osteoblast/Osteoclast Monocytes/macrophages Nervous system Bone marrow Cardiovascular

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SLIDE 8

NH2

Signaling Pathways Activated by the CaSR

Phospholipase C Phospholipase C

Calcium Sensing Receptor (CaSR)

1 2 3 4 5 6 7

P P P P HCOO

Spurney RF, et al. Kidney Int 1999;55(5):1750-8.

Phospholipase C Phospholipase C (Inositol triphosphate, Ca (Inositol triphosphate, Ca2+

2+ i)

Phospholipase A2 Phospholipase A2 (Arachidonic acid) (Arachidonic acid)

Phospholipase D (Phosphatidic acid) Phospholipase D (Phosphatidic acid) MAP Kinase MAP Kinase Inhibition of Adenylate Cyclase Inhibition of Adenylate Cyclase

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SLIDE 9

DNA mRNA mRNA Storage

Transcripcion

Translation

Low Calcium

How Calcium Influence Parathyroid Hormone Synthesis ?

preproPTH

PTH

Storage Translation Degradacion

Secretion Silver et al, 2000-2002

Low Calcium Increases the Stability

  • f PTH mRNA

The Stability of PTHmRNA may vary from 5 minutes to 3 hours Post-transcriptional

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SLIDE 10

In CKD There is a Reduction of Expression of CaSR (40-60%)

The Calcium Sensing Receptor in CKD

N H 2

Reduction in Capacity of the Parathyroid Gland to Sense Ca

1 2 3 4 5 6 7

P P P P HCOO
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SLIDE 11

110 100 90 80 70

Normal Moderate Hyperparathyroidism

Severe Hyperparathyroidism Refractory Hiperparathyroidism

Changes in the PTH Response to Calcium with the Progression of Secondary Hyperparathyroidism ¿ Is the Decrease of Sensitivity of the Parathyroid Glands to Calcium “ Clinically Relevant”?

70 60 50 40 30 20 10 PTH (%) Ionized Ca (mmol/L) 1 1.1 1.2 1.3 1.4 1.5 1.6 Set point

Increments in “Non Suppressible” PTH Secretion Due to Gland Growth

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SLIDE 12

Parathyroid Gland Response to Calcium Changes in CKD 5

TH (pg / ml)

COSMOS Study: 4600 patients / 20 Countries

PTH Response to Calcium Changes in CKD 5 Progression of CKD-MBD Severely Affect the Response

  • f the Parathyroid Glands

95% IC PTH

>12 10.5-11 9.5-10 8-9 6-7

JL Fernández et al , ERA-EDTA, Stocholm, 2008

Serum Calcium (mg/dL)

  • f the Parathyroid Glands

to Calcium Serum Calcium May Influence Outcomes in Dialysis Patients

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SLIDE 13
  • Multi-centre, Open Cohort and Observational

Study.

  • Prospective: 3-year of follow-up.
  • European Focused (20 countries)
  • Size of the Sample: 4,500 HD Patients from 227

Centres Spread Geographically (medium-large

COSMOS: Una Fotografía del Escenario Europeo en CKD-MBD

Centres Spread Geographically (medium-large hospitals and satellite units)

  • Sites and Patients (±20 per centre) Randomly

selected Oviedo

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SLIDE 14

TH (pg / ml)

Parathyroid Gland Response to Calcium Changes in CKD 5

COSMOS Study: 4600 patients / 21 Countries

Calcimimetics Can Improve the Poor Response of the Parathyroid Glands to Calcium Increasing the Sensivity

  • f CaSR to Calcium

95% IC PTH

Serum Calcium (mg/dL)

>12 10.5-11 9.5-10 8-9 6-7

JL Fernández et al , ERA-EDTA, 2007

  • f CaSR to Calcium
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SLIDE 15

DNA mRNA mRNA preproPTH

PTH

Transcription

Translation

Calcimimetics Reduce PTH Synthesis Calcimimetics Decrease Cell Proliferation

% Reduction in Size PTH

Degradation

Consequences of the Action of Calcimimetics Calcimimetics Upregulate CaSR and VDR –Interaction and Cooperation-

< 500 mm3 > 500 mm3

60%

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SLIDE 16

110 100 90 80 70 60 50 40 PTH (%)

Improvement in the Parathyroid Response

“Set Point” Shift to the Left

Hiperparatiroidismo moderado

Effect of Calcimimetics

40 30 20 10 Ionized Ca (mmol/L) 1 1.1 1.2 1.3 1.4 1.5 1.6

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SLIDE 17

110 100 90 80 70 60 50 40 PTH (%)

Improvement in the Parathyroid Response

“Set Point” Shift to the Left

Hiperparatiroidismo moderado

Effect of Calcimimetics

40 30 20 10 Ionized Ca (mmol/L) 1 1.1 1.2 1.3 1.4 1.5 1.6

Curve May Be Push Down

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SLIDE 18

Rapid Non-Genomic Response Slow Genomic Response

? Ca2+, ?IP3, ? pH, PKC

  • 1,25-(OH)2D

Membrane Receptor VDR ? Ca2+, ?IP3, ? pH, PKC Transcription Factor Co-activators and co-represors

  • 1,25-(OH)2D

VDR Cell membrane

CITOPLASM CITOPLASM 2 Messanger

Effects of VDR Activation

  • VDRE

ARNm ARNm Co-activators and co-represors

  • VDRE

VDRE ARNm ARNm Nuclear membrane

Protein Protein

NÚCLEUS NÚCLEUS Transcription Transcription

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SLIDE 19

? Ca2+, ?IP3, ? pH, PKC

  • 1,25-(OH)2D

Membrane Receptor VDR ? Ca2+, ?IP3, ? pH, PKC Transcription Factor Co-activators and co-represors

  • 1,25-(OH)2D

VDR Cell membrane

CITOPLASMA CITOPLASM 2 Messanger

Osteopontin Osteocalcin RANK-L VDR

Proteins Regulated by VDR Activation

Cbf1 BMP-2 PTH Collagen 1α hydroxilase Renin

Down Regulated

Slow Genomic Response

Effects of VDR Activation

  • VDRE

ARNm ARNm Co-activators and co-represors

  • VDRE

VDRE ARNm ARNm Nuclear membrane

Proteina Protein

NÚCLEO NÚCLEUS Transcription Transcription

Multiple Proteins are Regulated by VDR Activation

VDR 24-hydroxilase Calbindin TRPV5-6 IL-10, IL-4 Insulin p-21, p-27

Up Regulated

Renin IFN-γ IL-Iβ, IL-2, -6, - 12 Ciclin E Gen C-myc

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SLIDE 20

Parathyroid Glands

Kidney Bone Intestine

Bone and Mineral

Cardiovascular System

Myocardial Structure Myocardial Function Vascular System

  • Arterial Pressure
  • Vascular Function
  • Immune System

Effects of VDR Activation

  • Immune System
  • Infections-
  • Inflammatory Response
  • Skin
  • Muscular System
  • Antiproliferative effect
  • Cancer-
  • Renoprotection

Survival

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SLIDE 21

1,5 No vitamin D

Relaytive Risk (RR)

The Better Results Were Obtained With Dose < 1 mcg/day

CORES

VDR Activation and Survival

1 0,75 No vitamin D 0,50 0,25

0,54 (0,46-0,63)

< 0.25ug/d

(n=1.304)

0.25-0,50µg/d

(n=1.053)

> 0.50-1 µg/d

(n=432)

0,60 (0,51-0,72) 0,66 (0,51-0,85)

> 1 µg/d

(n=184)

0,74 (0,52-1,05)

Obtained With Dose < 1 mcg/day Vitamin D

Benefits of Oral Active VDR Activators on Survival

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SLIDE 22

Main Factors Influencing the VDR Response

Adequate VDR Expression

Mechanisms of CKD-MBD: New Insights in the Pathogenesis

Optimal Concentration of VDR Activator

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SLIDE 23

DNA mRNA mRNA Storage

Transcription

Translation

Transcription

Calcitriol Deficit VDR Expression in CKD No Inhibition of PTH Gene Transcription

preproPTH

PTH

Storage Translation Degradation

VDR

Decreased Expression of VDR

Secretion

Increase mRNA PTH Synthesis

Transcriptional

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SLIDE 24

DNA mRNA mRNA Storage

Transcription

Translation

Administration

  • f Calcitriol

218,7±42,6 * 100,0 50 100 150 200 250 300 mRNA VDR/18s (%)

Expression

  • f VDR

Inhibition of PTH Gene Transcription

Normalize Serum Calcitriol Levels

VDR Expression in CKD

Cooperation Between

VDR & CaSR

Reduce

preproPTH

PTH

Storage Translation Degradation

Parathyroid Glands Culture

50 Control Calcitriol 10-8M

Reduce PTH Synthesis

212,8±39,9 * 100,0 50 100 150 200 250 300 Control Calcitriol 10-8M mRNA CaR/18s (%)

Expression

  • f CaSR
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SLIDE 25

Main Factors Influencing the VDR Response

Adequate Concentration of VDR

Mechanisms of CKD-MBD: New Insights in the Pathogenesis

Optimal Concentration of VDR Activator

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SLIDE 26

50 40 30

1,25D

60 70 80 90 100 levated PTH (%)*

CKD Stage 2 Stage 3

lcitriol

2D3 (pg/mL)

Stage 4

  • Lower range
  • f 1,25D

Optimal Concentration of VDR Activator -CALCITRIOL- ?

A Levin et al KI 2007 GFR (mL/min/1.73 m2) 20 10 105 95 75 85 65 45 35 15 55 25 10 20 30 40 50 Patients With Ele Calc 1,25(OH)2

  • Why and When

the Calcitriol Reduction Start in CKD ?

  • f 1,25D
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SLIDE 27

50 40 30

1,25D

60 70 80 90 100 levated PTH (%)*

CKD Stage 2 Stage 3

lcitriol

2D3 (pg/mL)

Stage 4

  • Lower range
  • f 1,25D ?

Serum Calcitriol Levels in Early CKD

A Levin et al KI 2007 GFR (mL/min/1.73 m2) 20 10 105 95 75 85 65 45 35 15 55 25 10 20 30 40 50 Patients With Ele Calc 1,25(OH)2

  • Posible Effect of Early

Increase of FGF23 in CKD

  • f 1,25D ?

Why and When the Calcitriol Reduction Start in CKD ?

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SLIDE 28

PTH Urinary P

PTH (+) (-)

Calcitriol Phoshorus Calcium

(-) (+)

FGF 23

(-)

(-) 1 alpha Hydroxylase

(+) 24,25 alpha Hydroxilase

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SLIDE 29

PTH Urinary P

PTH (+) (-) (+)

Consequence

Calcitriol Phoshorus Calcium

(-) (+)

FGF 23

(-)

(-) 1 alpha Hydroxylase

(+) 24,25 alpha Hydroxilase

?

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SLIDE 30

50 40 30

1,25D

60 70 80 90 100 levated PTH (%)*

CKD Stage 2 Stage 3

lcitriol

2D3 (pg/mL)

Stage 4

  • Lower range
  • f 1,25D

Serum Calcitriol Levels in Early CKD

GFR (mL/min/1.73 m2) 20 10 105 95 75 85 65 45 35 15 55 25 10 20 30 40 50 Patients With Ele Calc 1,25(OH)2

  • f 1,25D

FGF 23 Through its Capacity to Reduce Calcitriol Could Be an Important Indirect Factor “Early” Involved in the Pathogenesis of Secondary Hyperparathyroidism

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SLIDE 31

Indirect Factor ?

PTH ?

2007

control

(-) (-) (+)

FGF 23 Calcitriol

Phosphorus

Calcium

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SLIDE 32

P < 0.001 P = 0.02

FGFR1 and Klotho Score

Grade 4 Grade 3 Grade 2 Grade 1

FGF23 Do Not Decrease PTH in Advanced SHPT

In Advanced CKD There is a Resistance to the Effect of FGF 23

4 3 2

P = 0.055

Normal

Nodular s/o > 0.5 g

Klotho score

1

P = 0.013

Diffuse s/o < 0.5 g

4 3 2

P = NS

Normal

Nodular s/o > 0.5 g

FGFR1 score

1

P = NS

Diffuse s/o < 0.5 g

Komaba, Fukagawa: Kidney Int 2010;77 232-238

FGFR1 Klotho

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SLIDE 33

FGF23 Do Not Decrease PTH in Advanced SHPT

In Advanced CKD There is a Resistance to the Effect of FGF 23

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SLIDE 34

PTH

Last Decade Phosphorus Have Increased its Importance in PTH Regulation and CKD-MBD Mechanisms of CKD-MBD: New Insights in the Pathogenesis

Calcitriol Phosphorus Calcium

Regulation and CKD-MBD

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SLIDE 35

Outcomes

  • Vascular Calcifications
  • Lack of Response to

Vit D Metabolites

  • Increased Mortality

Ngative Effects of Phosphorus

2012: Combination/ Association of

  • Increased Mortality
  • Decrease in Cortical Bone*
  • Decrease in Bone Mass*
  • Decrease in Bone Strength*
  • Pro-Inflamatory
  • Pro-Ageing Element

Makoto Kuro-O. Avances en Metabolismo Óseo y Mineral, Edited by JB Cannata-Andía y col, 2010

Association of Effects of Phosphorus & FGF 23

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SLIDE 36

Na-Pi 2a Na-Pi 2c

Proximal Kidney Tubule Cells

PTH

Mechanisms of CKD-MBD: New Insights in the Pathogenesis

Klotho

FGF-R

Calcitriol Phosphorus Calcium

25(OH)D

(-) (-) (+)

FGF 23

FGF-23

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SLIDE 37

PTH Urinary Phosphate

PTH (+)

Urinary Phosphate

Calcitriol Phosphorus Calcium

25(OH)D

(-) (-) (+)

FGF 23

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SLIDE 38

PTH Urinary Phosphate

PTH (+)

¿ Cuáles son las Sinergias Entre Fósforo, FGF 23, Kotho y Vitamina D ?

mmol/L

Creatinine Clearance

0.75 1.00 1.25 1.50

Phosphorus

0.50

Urinary Phosphate

Calcitriol Phosphorus Calcium

25(OH)D

(-) (-) (+)

FGF 23

(-)

(-)1 alpha Hydroxylase

(+) 24,25 alpha Hydroxilase

5 Mechanisms

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SLIDE 39

DNA mRNA mRNA Storage

Transcription

Translation

High Phosphorus Increases PTH Synthesis

Effect of Phosphorus on the Parathyroid Glands in CKD

preproPTH

PTH

Storage Translation Degradation

Silver et al, 2000-2002 Secretion

Post -transcriptional

High Phosphorus

Increases the Stability

  • f PTH mRNA
slide-40
SLIDE 40

Decrease CaSR Expression

Effect of Phosphorus in Cell Proliferation and CaSR

THE HIGHER THE PHOSPHORUS CONCENTRATION

  • THE GREATER THE DIRECT STIMULATION OF PTH SYNTHESIS

Increase Cell Proliferation

Brown AJ. Kidney Int 55:1284 Brown AJ. Kidney Int 55:1284-

  • 1292, 1999

1292, 1999

  • THE GREATER THE DIRECT STIMULATION OF PTH SYNTHESIS

THE GREATER THE CELL PROLIFERATION (Gland Growth) AND THE LOWER THE CaSR EXPRESSION

¿ Is the Effect of High Serum Phosphorus on the Parathyroid Glands “Clinically Relevant” ?

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SLIDE 41

High Serum Phosphorus and PTH in CKD 5 Patients

PTH (pg / ml)

600 500 400

Serum Ca (mg/dL)

> 12 10.5-11 9.5-10 8-9 6-7

95% IC PT

>10 9-9.9 8-8.9 7-7.9 6-6.9 5-5.9 4-4.9 3-3.9 1-2.9 300 200 100

Serum P (mg / dl)

JL Fernández et al , ERA-EDTA, 2007

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SLIDE 42

PTH (pg / ml)

600 500 400

Serum Phosphorus is the Strongest Factor Associated to PTH High Serum Phosphorus and PTH in CKD 5 Patients

95% IC PT

>10 9-9.9 8-8.9 7-7.9 6-6.9 5-5.9 4-4.9 3-3.9 1-2.9 300 200 100

Serum P (mg / dl)

Associated to PTH Levels in CKD 5

Serum Phosphorus May Influence Outcomes in Dialysis Patients

JL Fernández et al , ERA-EDTA, 2007

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SLIDE 43

PTH FGF23/Klotho

Progression of Secondary Hyperparthyroidism Calcitriol

Phosphorus 25(OH)D

Cannata –Andía JBy Rodriguez M.. Nefrología Clínica . Ed L Hernando, 2008,

Calcium

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SLIDE 44

VDR CaR

Polyclonal:

Gland size

Progression of Secondary Hyperparthyroidism

Nodular

Monoclonal:

VDR

CaR Klotho/FGFR1

Normal Diffuse Secretory cells

Adapted from Tominaga Y et al. Curr Opin Nephrol Hypertens 1996;5:336–41

Progression of Secondary Hyperparathyroidism

Early nodularity Late-single nodularity

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SLIDE 45

VDR CaR

Polyclonal:

Nodular

Monoclonal:

VDR CaR

  • Severe Molecular Changes
  • Genomic Alterations

Progression of Secondary Hyperparthyroidism

Normal Diffuse Secretory cells

Adapted from Tominaga Y et al. Curr Opin Nephrol Hypertens 1996;5:336–41

Progresión del Hiperparatiroidismo Secundario

Early nodularity Late-single nodularity

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SLIDE 46

VDR CaR

Polyclonal:

Nodular

Monoclonal:

VDR CaR Duplications Losses

Losses & Duplications of Chromosomes

J Cigudosa , I Santamaría , J Cannata et al

Parathyroid Tissue from Severe 2ª & 3ª Hyperparathyroidism

Progression of Secondary Hyperparthyroidism

Normal Diffuse Secretory cells

Progresión del Hiperparatiroidismo Secundario

Early nodularity Late-single nodularity

Adapted from Tominaga Y et al. Curr Opin Nephrol Hypertens 1996;5:336–41

J Cigudosa , I Santamaría , J Cannata et al Kidney Int 2003: 63,

Changes in Gene Expression

Control Difusas Nodulares Control Difusas Nodulares

I Santamaría et al Kidney Int, 2005.

Gene Repression

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SLIDE 47

VDR CaR

Polyclonal:

Nodular

Monoclonal:

VDR CaR

Calcificaciones Vasculares

  • Mala Evolución Clínica

The Parathyroid Glands Progresively Loose its Complex and

Progression of Secondary Hyperparthyroidism Just Produce

PTH

Normal Diffuse Secretory cells

Adapted from Tominaga Y et al. Curr Opin Nephrol Hypertens 1996;5:336–41

Progresión del Hiperparatiroidismo Secundario

Early nodularity Late-single nodularity

Calcificaciones Vasculares Mortalidad Fracturas

PTH

Exquisite Regulatory Leadership Role

PTH

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SLIDE 48
  • Role of Classic and New Players in the Pathogenesis
  • f Secondary Hyperparathyroidism and CKD-MB

Role of * Calcium (Calcimimetics) * Vitamin D Receptor Activators (VDRAs) * Phosphorus and FGF 23

Mechanisms of CKD-MBD: New Insights in the Pathogenesis

* Phosphorus and FGF 23 * Genomic & Molecular Changes in the Severe and Refractory Secondary Hyperparathyroidism

  • The Links Between the Bone and Vascular Axis in CKD-MBD.

Role of Phosphate in the Pathogenesis of Vascular Mineralization and Bone Demineralization. Possible Self-defensive Mechanisms Triggered by the Vascular System

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SLIDE 49

HIGH BONE TURNOVER

Current Evolution

High PTH

Patterns of Renal Osteodystrophy

CKD

MEDICAL MANAGEMENT

DIABETES - AGE

LOW BONE TURNOVER

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SLIDE 50

Moriniere et al, 1989 (France)

76 % 24 %

Lorenzo et al, 1991 (Spain)

71% 25 %

Sherrard et al, 1993 (USA)

48 % 37 %

Change in the Prevalence of High and Low Bone Turnover Disease in CKD5

Low Bone Turnover High Bone Turnover

1/4 3/4

Sherrard et al, 1993 (USA)

48 % 37 %

Herz et al, 1993 (USA)

50 % 50 %

Torres et al, 1995 (Spain)

52 % 45 %

Ferreira et al 2008 (Portugal)

32 %

63 %

Erkan, Gulay et al 2009(Turkey)

23%

73 % 1/4 3/4

slide-51
SLIDE 51

High Bone Turnover Low Bone Turnover

Common Risks

Risks of High and Low Bone Turnover Vascular Calcifications Mortality

Bone Mass Fractures

slide-52
SLIDE 52

J Am Soc Nephrol 15: 1943-1951,2004

Bone Turnover

CKD

Relationship Between Vascular Calcification & Bone High Calcification Scores in the Aorta Low Bone Activity

slide-53
SLIDE 53

Coronary Calcification is Associated with Lower Mineralized Bone Volume

CKD

Relationship Between Vascular Calcification & Bone

Coronary Calcification Low Mineralized Bone High Pulse Wave Velocity

10 20 30

%

10 20 30

%

Pulse Wave Velocity

> 9.4 ≤ ≤ ≤ ≤ 9.4 > 400 ≤ ≤ ≤ ≤ 400

p=0.03 p=0.02

Mineralized bone volume Mineralized bone volume

Coronary Agatston score

slide-54
SLIDE 54

Relationship Between Vessels & Bone

General Population

CKD

slide-55
SLIDE 55

Relationship Between Vessels & Bone

Osteoporos Int 19: 1161-1166, 2008

4 Years Follow up

General Population

General Population

4 Years Follow up

slide-56
SLIDE 56

From Patient to Bench Relationship Between Vascular Calcification & Bone

CKD

General Population

Osteoporos Int 19: 1161-1166, 2008

?

slide-57
SLIDE 57

Week 4 Week 8 Week 16 Week 20 Week Week 12

N 5/6

Scheme of the Study

Relationship Between Vascular Calcification & Bone

4 8 16 20 Normal (n=10)

High P (n=10)

Control (n=10)

High P (n=10)

Control (n=10)

High P (n=10)

Control (n=10)

High P (n=10)

Control (n=10) Normal (n=10) 12

High P (n=10)

Control (n=10)

Aorta Bone

Macroscopic Histologic

Genomics Proteomics

High P High Mortality

50% Vs 10%

slide-58
SLIDE 58

Aortic Calcification (20 weeks) 20%

NO Aortic Calcification (20 weeks)

High Phosphorus Diet (+ 50%)

Relationship Between Vascular Calcification & Bone

High Phosphorus Diet (+ 50%)

80%

Román-García et al. Bone 2010:46; 121-128.

slide-59
SLIDE 59

Bone Histology

20%

Relationship Between Vascular Calcification & Bone

80%

Román-García et al. Bone 2010:46; 121-128.

Vascular Calcification Bone No Vascular Calcification Bone

slide-60
SLIDE 60

Week 4 Week 8 Week 16 Week 20 Week Week 12

N 5/6

Scheme of the Study

Relationship Between Vascular Calcification & Bone

4 8 16 20 Normal (n=10)

High P (n=10)

Control (n=10)

High P (n=10)

Control (n=10)

High P (n=10)

Control (n=10)

High P (n=10)

Control (n=10) Normal (n=10) 12

High P (n=10)

Control (n=10)

Aorta Bone Macroscopic Histologic

Genomics Proteomics

slide-61
SLIDE 61

Elastin

  • 1
  • 0,5

0,5 FC 8NP FC 16NP FC 20NP FC 8HP FC 16HP FC 20HP ld Change

Elastin

Muscle Related Genes

Muscle Related Genes

No Calcification

Red: Overexpression

Calcification

Gene

Gene Expression Profile in Aorta

  • f Rats with Vascular Calcification

Tropomyosin, Alpha 1

  • 2
  • 1,5
  • 1
  • 0,5

0,5 FC 8NP FC 16NP FC 20NP FC 8HP FC 16HP FC 20HP Fold Change

Tropomyosin Alpha 1

  • 2
  • 1,5
  • 1

Fold

  • 1.5 +1.5

Signal LogRatio

Green: Repression

Gene

Román-García et al. Bone 46: 121-128; 2010

slide-62
SLIDE 62

Red: Overexpression

Bone Related Genes

RED: Overexpression

Calcification No Calcification

Gene Muscle Related Genes

No Calcification Calcification

Gene Expression Profile in Aorta

  • f Rats with Vascular Calcification
  • 1.5 +1.5

Signal LogRatio

Green: Repression

  • 1.5 +1.5

Signal LogRatio

Green: Repression

Gene

Román-García et al. Bone 46: 121-128; 2010

slide-63
SLIDE 63

SFRP-1

1,5 2 2,5 Change

SRFP 4 (Wnt)

Bone Related Genes Bone Related Genes

RED: Overexpression

Calcification No Calcification

Gene Expression Profile in Aorta

  • f Rats with Vascular Calcification

Katepsin K

Cathepsin K

0,5 1 1,5 2 FC 8NP FC 16NP FC 20NP FC 8HP FC 16HP FC 20HP Fold Change

  • 0,5

0,5 1 FC 8NP FC 16NP FC 20NP FC 8HP FC 16HP FC 20HP Fold Ch

  • 1.5 +1.5

Signal LogRatio

Green: Repression

Román-García et al. Bone 46: 121-128; 2010

slide-64
SLIDE 64

Bone Related Genes

SFRP-1

1,5 2 2,5 Change

SRFP 4 (Wnt)

Gene Expression Profile in Aorta

  • f Rats with Vascular Calcification

?

In the Calcified Aorta: Markers of Active Bone Resorption & Inhibition of Bone Formation

Katepsin K

Cathepsin K

0,5 1 1,5 2 FC 8NP FC 16NP FC 20NP FC 8HP FC 16HP FC 20HP Fold Change

  • 0,5

0,5 1 FC 8NP FC 16NP FC 20NP FC 8HP FC 16HP FC 20HP Fold Ch

Román-García et al. Bone 46: 121-128; 2010 Bone Resorption

?

Defensive Mechanism

slide-65
SLIDE 65

? SFRPs

Dkk 1

Aorta

Wnt and BMP Inhibition

Vessels: Reduce or Stop Vascular Mineralization

Price to Pay ? Relationship Between Vascular Calcification & Bone

Which is Molecular the Link ?

Gremlin Bone: Decrease Bone Mineralization and Bone Mass