Mechanisms of CKD-MBD: New insights in the pathogenesis · Mechanisms of CKD-MBD: New insights in...

Mechanisms of CKD-MBD:

New insights in the pathogenesis

Mechanisms in chronic kidney disease

Jorge Cannata-Andia

University of Oviedo

Oviedo, Spain

• Role of Classic and New Players in the Pathogenesis of Secondary Hyperparathyroidism and CKD-MBRole 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 Mineralizationand Bone Demineralization. Possible Self-defensive Mechanisms Triggered by the Vascular System

MEDICINE 22: 103-161; 1943

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

• Secondary Hyperparathyroidism• Osteomalacia• Osteosclerosis• Osteoporosis


1970’s – 1980’s: PTH Assays and Bone BiopsyDiagnosis 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

Kidney Disease Improving Global Outcomes


RenalOsteodystrophy

SecondaryHyperparathyroidism

the Vessels & BonePlay Important Role

PTH

FGF23/Klotho

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

Parathyroid Regulation in Chronic Kidney Disease

Calcitriol Phosphorus

25(OH)DCannata –Andía JBy Rodriguez M.. Nefrología Clínica . Ed L Hernando, 2008,

FGF23/Klotho

Calcium

PTH

FGF23/Klotho

Parathyroid Regulation in Chronic Kidney Disease

CaSRCaSR 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, .......


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

FGF23/Klotho

Calcium

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

NH2

Signaling Pathways Activated by the CaSR

Phospholipase C Phospholipase C

Calcium Sensing Receptor (CaSR)

1 2 3 4 5 6 7

P

PP

P

HCOO

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

Phospholipase C Phospholipase C (Inositol triphosphate, Ca(Inositol triphosphate, Ca2+2+

ii))

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

Phospholipase D (Phosphatidic acid)Phospholipase D (Phosphatidic acid)MAP KinaseMAP Kinase

Inhibition of Adenylate CyclaseInhibition of Adenylate Cyclase

DNA

mRNA

mRNA

Storage

Transcripcion

Translation

Low Calcium

How Calcium Influence Parathyroid Hormone Synthesis ?

preproPTH

PTH

StorageTranslation

Degradacion

Secretion

Silver et al, 2000-2002

Low CalciumIncreases the Stability

of PTH mRNA

The Stability of PTHmRNA may vary from

5 minutes to 3 hoursPost-transcriptional

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

The Calcium Sensing Receptor in CKD

NH2

Reduction in Capacity of theParathyroid Gland to Sense Ca

1 2 3 4 5 6 7

P

PP

P

HCOO

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

0

PT

H (

%)

Ionized Ca (mmol/L)

1 1.1 1.2 1.3 1.4 1.5 1.6

Set point

0

Increments in “Non Suppressible”

PTH Secretion Due toGland Growth

Parathyroid Gland Response to Calcium Changes in CKD 5

PT

H (p

g /

ml)

COSMOS Study: 4600 patients / 20 Countries

PTH Response to Calcium Changes in CKD 5

Progression of CKD-MBDSeverely Affectthe Response

of the Parathyroid Glands

95%

IC P

TH

>1210.5-11

9.5-108-9

6-7

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

Serum Calcium (mg/dL)

of the Parathyroid Glandsto Calcium

Serum Calcium May Influence Outcomes in Dialysis Patients

• 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 CentresSpread Geographically (medium-large

COSMOS: Una Fotografía delEscenario Europeo en CKD-MBD

CentresSpread Geographically (medium-large hospitals and satellite units)

• Sites and Patients (±20 per centre) Randomly selected

Oviedo

PT

H (p

g /

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 CalciumIncreasing the Sensivity

of CaSR to Calcium

95%

IC P

TH

Serum Calcium (mg/dL)

>1210.5-11

9.5-108-9

6-7

JL Fernández et al , ERA-EDTA, 2007

of CaSR to Calcium

DNA

mRNA

mRNA

preproPTH

PTH

Transcription

Translation

Calcimimetics Reduce PTH Synthesis Calcimimetics

Decrease Cell Proliferation

% Reduction in SizePTHDegradation

Consequences of the Action of Calcimimetics

Calcimimetics Upregulate CaSR and VDR–Interaction and Cooperation- < 500 mm3 > 500 mm3

60%

110

100

90

80

70

60

50

40

PT

H (

%)

Improvement in the Parathyroid Response

“Set Point” Shift to the Left

Hiperparatiroidismo moderado

Effect of Calcimimetics

40

30

20

10

0

Ionized Ca (mmol/L)

1 1.1 1.2 1.3 1.4 1.5 1.60

110

100

90

80

70

60

50

40

PT

H (

%)

Improvement in the Parathyroid Response

“Set Point” Shift to the Left

Hiperparatiroidismo moderado

Effect of Calcimimetics

40

30

20

10

0

Ionized Ca (mmol/L)

1 1.1 1.2 1.3 1.4 1.5 1.60

Curve MayBe Push

Down

Rapid Non-Genomic Response Slow Genomic Response

? Ca2+, ?IP3, ? pH, PKC

- -

1,25-(OH)2D

Membrane Receptor

VDR? Ca2+, ?IP3, ? pH, PKC

Transcription FactorCo-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- -

VDREVDRE

ARNm ARNm

Nuclear membrane

Protein Protein

NÚCLEUS NÚCLEUSTranscription Transcription

? Ca2+, ?IP3, ? pH, PKC

- -

1,25-(OH)2D

Membrane Receptor

VDR? Ca2+, ?IP3, ? pH, PKC

Transcription FactorCo-activators and co-represors- -

1,25-(OH)2D

VDR

Cell membrane

CITOPLASMA CITOPLASM

2 MessangerOsteopontin OsteocalcinRANK-L VDR

Proteins Regulated by VDR Activation

Cbf1 BMP-2 PTH Collagen 1α hydroxilase Renin

Down Regulated

Slow Genomic Response


- -

VDRE

ARNm ARNm

Co-activators and co-represors- -

VDREVDRE

ARNm ARNm

Nuclear membrane

Proteina Protein

NÚCLEO NÚCLEUSTranscription Transcription

Multiple Proteins are Regulated by VDR Activation

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

Up Regulated

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

� Parathyroid Glands

� Kidney� Bone

� Intestine� Bone and Mineral � Cardiovascular System

� Myocardial Structure� Myocardial Function� Vascular System

- Arterial Pressure- Vascular Function

� Immune System


� Immune System -Infections-

� Inflammatory Response� Skin � Muscular System� Antiproliferative effect

-Cancer-� Renoprotection

Survival

1,5No 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

Main Factors Influencing the VDR Response

� Adequate VDR Expression


� Optimal Concentration of VDR Activator

DNA

mRNA

mRNA

Storage

Transcription

Translation

TranscriptionCalcitriolDeficit

VDR Expression in CKD

No Inhibition of PTHGene Transcription

preproPTH

PTH

StorageTranslation

Degradation

VDR

Decreased Expression of VDR

Secretion

Increase mRNA PTH

Synthesis

Transcriptional

DNA

mRNA

mRNA

Storage

Transcription

Translation

Administration of Calcitriol

218,7±42,6*

100,0

50

100

150

200

250

300

mR

NA

VD

R/1

8s (

%) Expression

of VDRInhibition of PTHGene Transcription

Normalize Serum Calcitriol Levels

VDR Expression in CKD

Cooperation Between VDR & CaSR

Reduce preproPTH

PTH

StorageTranslation

DegradationParathyroid Glands Culture

0

50

Control Calcitriol 10-8M

Reduce PTH

Synthesis212,8±39,9

*

100,0

0

50

100

150

200

250

300

Control Calcitriol 10-8M

mR

NA

CaR

/18s

(%

) Expressionof CaSR

Main Factors Influencing the VDR Response

� Adequate Concentration of VDR


� Optimal Concentration of VDR Activator

50

40

30

1,25D

60

70

80

90

100

Pat

ien

ts W

ith

Ele

vate

d P

TH

(%

)*CKD Stage 2 Stage 3

Cal

citr

iol

2D3

(pg

/mL

)

Stage 4●●●●

●●●●●●●●

●●●●

●●●●

Lower range of 1,25D

� Optimal Concentration of VDR Activator -CALCITRIOL- ?

A Levin et al KI 2007

GFR (mL/min/1.73 m2)

20

10

0105 95 7585 65 45 35 1555 25

10

20

30

4050

Pat

ien

ts W

ith

Ele

vate

d P

TH

(%

)*

Cal

citr

iol

1,25

(OH

) 2

●●●●

●●●●●●●●

●●●●

●●●●

Why and Whenthe Calcitriol

Reduction Start in CKD ?

of 1,25D

50

40

30

1,25D

60

70

80

90

100

Pat

ien

ts W

ith

Ele

vate

d P

TH

(%


Cal

citr

iol

2D3

(pg

/mL

)

Stage 4●●●●

●●●●●●●●

●●●●

●●●●

Lower range of 1,25D ?

Serum Calcitriol Levels inEarly CKD

A Levin et al KI 2007


20

10

0105 95 7585 65 45 35 1555 25

10

20

30

4050

Pat

ien

ts W

ith

Ele

vate

d P

TH

(%

)*

Cal

citr

iol

1,25

(OH

) 2

●●●●

●●●●●●●●

●●●●

●●●●

Posible Effect of Early Increase of FGF23 in CKD

of 1,25D ?

Why and Whenthe Calcitriol

Reduction Start in CKD ?

PTHUrinary P

PTH

(+)

(-)

Calcitriol Phoshorus

Calcium

(-)(+)

FGF 23 (-) (-) 1 alpha Hydroxylase

(+) 24,25 alpha Hydroxilase

PTHUrinary P

PTH

(+)

(-)

(+)

Consequence

Calcitriol Phoshorus

Calcium

(-)(+)

FGF 23 (-) (-) 1 alpha Hydroxylase

(+) 24,25 alpha Hydroxilase

?

50

40

30

1,25D

60

70

80

90

100

Pat

ien

ts W

ith

Ele

vate

d P

TH

(%


Cal

citr

iol

2D3

(pg

/mL

)

Stage 4●●●●

●●●●●●●●

●●●●

●●●●

Lower range of 1,25D

Serum Calcitriol Levels inEarly CKD


20

10

0105 95 7585 65 45 35 1555 25

10

20

30

4050

Pat

ien

ts W

ith

Ele

vate

d P

TH

(%

)*

Cal

citr

iol

1,25

(OH

) 2

●●●●

●●●●●●●●

●●●●

●●●●

of 1,25D

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

Indirect Factor ?

PTH ?2007

control

(-)

(-)(+)

FGF 23


Calcium

P < 0.001P = 0.02

FGFR1 and Klotho Score

Grade 4Grade 3Grade 2Grade 1

FGF23 Do Not Decrease PTH in Advanced SHPT

In Advanced CKD There is a

Resistance to theEffect of FGF 23

43

2

0

P = 0.055

Normal Nodular s/o> 0.5 g

Klo

tho

sco

re1

P = 0.013

Diffuse s/o< 0.5 g

4

3

2

0

P = NS

Normal Nodular s/o> 0.5 g

FG

FR

1 sc

ore

1

P = NS

Diffuse s/o< 0.5 g

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

FGFR1 Klotho

FGF23 Do Not Decrease PTH in Advanced SHPT

In Advanced CKD There is a

Resistance to theEffect of FGF 23

PTHLast Decade Phosphorus

Have Increased itsImportance in PTH

Regulation and CKD-MBD



Calcium

Regulation and CKD-MBD

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

Na-Pi 2aNa-Pi 2c

Proximal Kidney Tubule Cells

PTH


Klo

tho

FGF-R


Calcium25(OH)D

(-)

(-)(+)

FGF 23

FGF-23

PTHUrinary

Phosphate

PTH

(+)

UrinaryPhosphate


Calcium25(OH)D

(-)

(-)(+)

FGF 23

PTHUrinary

Phosphate

PTH

(+)

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

0

mm

ol/L

Creatinine Clearance

0.75

1.00

1.25

1.50

Phosphorus0.50

UrinaryPhosphate


Calcium25(OH)D

(-)

(-)(+)

FGF 23 (-)

(-)1 alpha Hydroxylase

(+) 24,25 alpha Hydroxilase5 Mechanisms

DNA

mRNA

mRNA

Storage

Transcription

Translation

High Phosphorus

Increases PTH Synthesis

Effect of Phosphorus on the Parathyroid Glands in CKD

preproPTH

PTH

StorageTranslation

Degradation

Silver et al, 2000-2002

Secretion

Post -transcriptional

High PhosphorusIncreases the Stability

of PTH mRNA

Decrease CaSR Expression

Effect of Phosphorus in Cell Proliferation and CaSR

THE HIGHER THE PHOSPHORUS CONCENTRATION

• THE GREATER THE DIRECT STIMULATION OF PTH SYNTHES IS

Increase Cell Proliferation

Brown AJ. Kidney Int 55:1284Brown AJ. Kidney Int 55:1284--1292, 19991292, 1999

• THE GREATER THE DIRECT STIMULATION OF PTH SYNTHES ISTHE GREATER THE CELL PROLIFERATION (Gland Grow th)

AND THE LOWER THE CaSR EXPRESSION

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

High Serum Phosphorus and PTH in CKD 5 Patients

PT

H (p

g /

ml) 600

500

400

Serum Ca (mg/dL)

> 1210.5-11

9.5-108-9

6-7

95%

IC P

TH

>109-9.9

8-8.97-7.9

6-6.95-5.9

4-4.93-3.9

1-2.9

300

200

100

Serum P (mg / dl)


PT

H (p

g /

ml) 600

500

400

Serum Phosphorus is the Strongest Factor

Associated to PTH

High Serum Phosphorus and PTH in CKD 5 Patients

95%

IC P

TH

>109-9.9

8-8.97-7.9

6-6.95-5.9

4-4.93-3.9

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


PTH

FGF23/Klotho

Progression of Secondary Hyperparthyroidism


25(OH)D

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

Calcium

VDR

CaRPolyclonal:

Gland size


0Nodular

Monoclonal:

VDR

CaR Klotho/FGFR1

NormalDiffuseSecretory

cells

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

Progression of Secondary Hyperparathyroidism

Earlynodularity

Late-singlenodularity

VDR

CaRPolyclonal:

0Nodular

Monoclonal:VDR

CaR• Severe Molecular Changes

• Genomic Alterations



cells


Progresión del Hiperparatiroidismo Secundario

Earlynodularity


VDR

CaRPolyclonal:

0Nodular

Monoclonal:VDR

CaRDuplicationsLosses

Losses & Duplications ofChromosomes

J Cigudosa , I Santamaría , J Cannata et al

Parathyroid Tissue from Severe 2ª & 3ª Hyperparathyroidism



cells


Earlynodularity



J Cigudosa , I Santamaría , J Cannata et alKidney Int 2003: 63,

Changes inGene Expression

Con

trol

Difu

sas

Nod

ular

esC

ontro

lD

ifusa

sN

odul

ares

I Santamaría et al Kidney Int, 2005.

GeneRepression

VDR

CaRPolyclonal:

0Nodular

Monoclonal:VDR

CaR

Calcificaciones Vasculares

•Mala Evolución Clínica

The Parathyroid Glands

Progresively Loose its

Complex and


Just Produce

PTHNormal

DiffuseSecretorycells



Earlynodularity


Calcificaciones Vasculares

MortalidadFracturasPTH

Exquisite Regulatory

Leadership Role

PTH

• Role of Classic and New Players in the Pathogenesis of Secondary Hyperparathyroidism and CKD-MBRole of * Calcium (Calcimimetics)

* Vitamin D Receptor Activators (VDRAs)* Phosphorus and FGF 23


* 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 Mineralizationand Bone Demineralization. Possible Self-defensive Mechanisms Triggered by the Vascular System

HIGHBONE

TURNOVER

Current

EvolutionHigh PTH

Patterns of Renal Osteodystrophy

CKD

MEDICALMANAGEMENT

DIABETES - AGE

LOWBONE

TURNOVER

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

1/43/4

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

High Bone Turnover Low Bone Turnover

Common Risks

Risks of High and Low Bone Turnover

Vascular Calcifications

MortalityBone MassFractures

J Am Soc Nephrol 15: 1943-1951,2004

Bone TurnoverCKD

Relationship Between Vascular Calcification & Bone

High Calcification Scores in the Aorta

Low Bone Activity

Coronary Calcification is Associated with Lower Mineralized Bone Volume

CKD


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

Min

eral

ized

bo

ne

volu

me

Min

eral

ized

bo

ne

volu

me

Coronary Agatston score

Relationship Between Vessels & Bone

General Population

CKD

Relationship Between Vessels & Bone

Osteoporos Int 19: 1161-1166, 2008

4 Years Follow up

General Population

General Population

4 Years Follow up

From Patient to Bench


CKD

General Population

Osteoporos Int 19: 1161-1166, 2008

?

Week4

Week8

Week16

Week20

Week0

Week12

N 5/6

Scheme of the Study


4 8 16 200Normal (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)

12High P (n=10)Control (n=10)

Aorta

Bone

Macroscopic

Histologic

Genomics

Proteomics

High P

High Mortality50% Vs 10%

Aortic Calcification (20 weeks)

20%NO Aortic

Calcification (20 weeks)

High PhosphorusDiet (+ 50%)


High PhosphorusDiet (+ 50%)

80%

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

Bone Histology

20%


80%

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

VascularCalcification

Bone

No VascularCalcification

Bone

Week4

Week8

Week16

Week20

Week0

Week12

N 5/6

Scheme of the Study


4 8 16 200Normal (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)

12High P (n=10)Control (n=10)

Aorta

Bone

Macroscopic

Histologic

Genomics

Proteomics

Elastin

-1

-0,5

0

0,5

FC 8NP FC 16NP FC 20NP FC 8HP FC 16HP FC 20HP

Fo

ld C

han

ge

Elastin

Muscle Related GenesMuscle Related Genes

No CalcificationRed: Overexpression

Calcification

Gene

Gene Expression Profile in Aorta of Rats with Vascular Calcification

Tropomyosin, Alpha 1

-2

-1,5

-1

-0,5

0

0,5


Fo

ld C

han

ge

Tropomyosin Alpha 1

-2

-1,5

-1

Fo

ld C

han

ge

-1.5 +1.5

Signal LogRatioGreen: Repression

Gene

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

Red: Overexpression

Bone Related Genes

RED: Overexpression

CalcificationNo

Calcification

Gene

Muscle Related Genes

No CalcificationCalcification


-1.5 +1.5


-1.5 +1.5


Gene


SFRP-1

1,5

2

2,5

Fo

ld C

han

ge

SRFP 4 (Wnt)

Bone Related GenesBone Related Genes

RED: Overexpression

CalcificationNo

Calcification


Katepsin K

Cathepsin K

0

0,5

1

1,5

2


Fo

ld C

han

ge

-0,5

0

0,5

1


Fo

ld C

han

ge

-1.5 +1.5



Bone Related Genes

SFRP-1

1,5

2

2,5

Fo

ld C

han

ge

SRFP 4 (Wnt)


?In the Calcified Aorta:

Markers ofActive Bone Resorption &

Inhibition of Bone Formation

Katepsin K

Cathepsin K

0

0,5

1

1,5

2


Fo

ld C

han

ge

-0,5

0

0,5

1


Fo

ld C

han

ge


Bone Resorption

?

Defensive

Mechanism

?

SFRPs

Dkk 1

Aorta

Wnt and BMP Inhibition

Vessels: Reduce or Stop Vascular Mineralization

Price to Pay ?


Which is Molecular the Link ?

GremlinBone: Decrease Bone

Mineralization

and Bone Mass

Mechanisms of CKD-MBD: New insights in the pathogenesis · Mechanisms of CKD-MBD: New insights in...

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