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Page 1: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

Interactions between bone and the central nervous system

Florent Elefteriou, PhD

Department of MedicineCenter for Bone Biology

VANDERBILT UNIVERSITYNashville, USA

Page 2: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

EstrogenEstrogen

BONE REMODELING

Osteoclasts Osteoblasts

Bone marrow cells

EstrogenCalcitonin

InsulinIGF1PTH

PTHrPBMP

...

BONE RESORPTION BONE FORMATION

MCSFRANKLEphrins

ILSDF1

Page 3: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

EstrogenEstrogen

BONE REMODELING

Osteoclasts Osteoblasts

Bone marrow cells

EstrogenCalcitonin

InsulinIGF1PTH

PTHrPBMP

...

BONE RESORPTION BONE FORMATION

MCSFRANKLEphrins

ILSDF1

NEURONAL CLUES

Page 4: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

• Traumatic brain injury promotes ectopic bone formation and bone healing

• Bone formation and resorption markers display circadian patterns

• Bone are innervated

• Stroke, spinal injury and peripheral neuropathies provoke bone loss

• Obesity is associated higher BMD

THE BONE AND BRAIN CONNECTION

Page 5: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

BONE REMODELING IS AN HOMEOSTATIC PROCESS

REGULATED BY

THE CENTRAL NERVOUS SYSTEM

HYPOTHESIS

Page 6: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

Adipocytes

Leptin

- Body weight- Reproduction- Immunity

WT ob/ob

A model of hypothalamic dysfunction:The ob/ob mice

Page 7: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

Leptin is an inhibitor of bone formation

WT ob/ob

14.0 ±0.4 19.4 ±0.6*Bone Vol. (%)64.6 ±18.0 110.3 ±15.2*BFR

Page 8: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

Does leptin inhibits bone formation via a central relay?

Leptin intracerebroventricular infusion (ICV)

(8 ng/h, 28 days treatment)

Page 9: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

Arcuate nucleus (Arc)

Ventromedial hypothalamus

(VMH)

3rd Ventricle3rd Ventricle

Central versus peripheral?

Page 10: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

PBS Leptin

18.3 ± 0.3 12.6 ± 0.7*Bone Vol. (%)

Central leptin delivery corrects the bone phenotype of ob/ob mice

Serum leptin(ng/ml)

0 0

Page 11: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

Arcuate nucleus (Arc)

Ventromedial hypothalamus

(VMH)

Leptin binds to ObRb in the hypothalamus

Page 12: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

Goldthioglucose destroys VMH neurons 

CONTROL GTG

Nissle stain

SF1

NPY

Page 13: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

VMH neuron destruction increases bone mass in WT mice

PBS GTG

Bone Vol. (%)

14.0 ± 0.6 19.3 ± 0.6*

ob/ob

19.4 ±0.6*

Page 14: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

Lack of ObRb in neurons, not osteoblasts, increases bone mass

(Synapsin-cre)(Coll I-cre)

Y. Shi and al, PNAS 2008

Page 15: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

Hypothalamic Y2R inhibits bone formation

P. Baldock and al, JCI 2002

Page 16: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

How does the hypothalamus regulate osteoblast function?

nerves

Soluble factor

Page 17: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

ICV

circulation

How does the hypothalamus regulate osteoblast function? 

Page 18: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

Bone vol.(%)

Leptin does not use a humoral pathwayto control bone mass

0

101112131415

PBS icv PBS partner Leptin icv Leptin partner

*

PBS icv PBS partner Leptin icv Leptin partner

Page 19: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

BONES ARE INNERVATED

• Neurons are detected in the bone micro-environment • Retrograde viruses injected in bone label

hypothalamic neurons

• Ob/ob mice have a low sympathetic tone

Neurofilament TH

Page 20: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

SNS

Osteoblast

Leptin

THE NEURONAL MODEL

Bone mass

?

Page 21: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

WT

BV/TV (%)

Dbh-/-

10.2 ±0.3 13.2 ±0.8*

Lack of catecholamines increases bone formation

BFR 82.3 ±4.5 105.4 ±5.8*

9.6 ±0.7 12.6 ±0.8*ObNb/BPm

Page 22: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

SNS

Osteoblast

Leptin

THE NEURONAL MODEL

Bone mass

?

Page 23: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

β2 β3 α1Aβ1

The β2‐Adrenergic receptors is expressed by osteoblasts

Gapdh

Adr

α1B α1C

Ob: Primary osteoblastsC: Positive control

Page 24: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

10100 0.01100

50

100

150

200

250

PBS Iso

Pro

NE PE PTHµΜ)

Iso Pro+

Induction of cAMP production by βAR agonists in osteoblasts 

1010 10

cAMP levelsFold

Induction

*

*

*

*

Page 25: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

17.8 ±0.6 11.7 ±0.6 *

β‐agonists decrease bone mass 

PBS Isoproterenol

Bone Vol. (%)

BFR/BS

ObNb/BPm

143.4 ± 7.7 109 ± 11.1*

18.2 ± 0.7 12.2 ± 2.2*

Page 26: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

WT

BV/TV (%)

β2AR-/-

11.9 ±0.9 17.9 ±1.1*

Lack of β2AR increases bone formation

BFR 253.8 ±20.3 354.1 ±1.1*

13.6 ±0.8 20.5 ±1.1*ObNb/BPm

normalBody weight normalnormalInsulin/leptin normal

Page 27: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

The SNS regulates osteoclastogenesis

28.0 ±0.8 23.6 ±1.5*

WT Adrβ2-/-

OcN/BPmOcS/BS

9.0 ±0.2 6.0 ±0.2*

Dpd 21.1 ±1.3 15.0 ±1.3

Page 28: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

How does β2AR signaling stimulate osteoclast differentiation?

Osteoblast

Osteoclast

2

1

“Osteoclastogenic”cytokines

Page 29: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

Clasts/well

PBS Iso PBS Iso

Osteoblasts:Osteoclast progenitors:

wtwt wt

-/-wtwt wt

-/-

Adrenergic signaling in osteoblasts ‐not osteoclasts‐

favors osteoclastogenesis

PBS

wt-/-

wt- /-

Iso0

200

600

1000* *

Page 30: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

Isoproterenol stimulates Rankl expression

1 2 4 6ISO - + +

WT Osteoblasts

Time (h)-

0

4

8

12

16Adrβ2-/- Osteoblasts

- - + + - + + - + + -PTH - - - - - + - - + - - + - - +

0

*

*

* ** *

Rankl expression (fold induction)

Page 31: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

PKA

Osteoblast

RanklATF4S-

cAMP

ATF4

β2AR

β2AR signaling in osteoblasts regulates Rankl expression via ATF4

Osteoclatogenesis

Elefteriou & al., Nature 2006

Page 32: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

Osteoblast

β2AR

β2AR signaling in osteoblasts regulates osteoblast proliferation via clock genes

PROLIFERATION

Fu & al., Cell 2005

CREB

Cyclin D1

ClockAP1 complex

c-mycc-myc

Page 33: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

SNS

Osteoblast

Leptin

THE NEURONAL MODEL

Bone mass

?

Page 34: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

WT Adrβ2-/-

Adrβ2-/-

WT

* *0

100

200

300

400

500

WT Adrβ2-/-

Adrβ2-/-

WT0

1 4

1 6

1 8

2 0PBSLeptin

*

Fat pad weight (mg)BV/TV (%)

Adrβ2 is required for leptin anti‐osteogenic function

Page 35: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

SNS

Osteoblast

Leptin

Are β‐blockers good for bones?

Bone mass

β‐blocker 

Page 36: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

13.8 ±0.3 16.2 ±0.8*

β‐blockers increase bone mass

PBS Propranolol

Bone Vol. (%)BFR 116.8 ± 6.3 169.3 ± 8.6*

NbOb/BPm 19.0 ± 1.4 26.7 ± 2.4*

Page 37: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

sham OVX

14.2 ± 0.8 12.1 ± 0.4*Bone Vol.(%)

14.1 ± 0.7

OVX+β-blocker

Propranolol prevents bone loss following ovariectomy

Page 38: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

HUMAN CLINICAL DATA

• 2006 Meta-analysis: 28.5% reduction in hip fracture risk (Wiens et al, 2006)

• Some studies reporting no effects• Confounding factors• # of patients• Long-term vs short-term• βAR selectivity/dose• Skeletal sites

Prospective studies are needed ($$$)

Page 39: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

What is the role of βAR signaling in bone pathophysiology and diseases?

BONE RESORPTIONBONE RESORPTION

BONE FORMATIONBONE FORMATION

HSC TRAFFICKINGHSC TRAFFICKING

βARβAR

OSTEOBLASTSOSTEOBLASTS

INSULIN SECRETIONINSULIN SECRETION

Elefteriou and al, Nature 2005

Elefteriou and al, Nature 2005 Hinoi and al, JCB 2009

Katayama and al, Cell 2006

SNS outflow Drugs

signaling

Page 40: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

PRE‐SYNAPTIC EFFECT: Depression and Bone Loss

• Major depression is associated with bone loss and increased fracture risk

• Associated with hypercorticolism and SNS activation

Page 41: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

Stress/depression decreases bone mass through SNS activation

Yirmiya and al, PNAS 2006

Page 42: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

POST‐SYNAPTIC EFFECT: The cannabinoid system 

Tam and al, Mol Pharm 2006

Page 43: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

CB1 STIMULATION IN PRE‐SYNAPTIC NEURONS INHIBITS NE RELEASE

Traumatic brain injury

2-AGNE

Osteoblasts

Neurons

β2AR

CB1

Tam and al., FASEB J., 20072-AG: 2-arachidonoyl glycerol

Page 44: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

SUMMARY

Diseases and clinical observations are great opportunities to unravel novel mechanisms

Multiple genetic mouse models are critical to address hypotheses raised by such clinical observations and to demonstrate mechanisms

Bone remodeling is regulated by the CNS and SNS

Drugs/diseases affecting SNS outflow or β2AR signaling in osteoblasts alter bone remodeling and bone mass

Page 45: Interactions between bone and the central nervous system · patterns • Bone are innervated ... VMH neuron destruction increases bone ... Depression and Bone Loss • Major depression

Post‐doctoral and student positions are open in the lab...

Department of MedicineCenter for Bone Biology

VANDERBILT UNIVERSITYNashville, USA

PROJECTS:

- SNS and bone- Skeletal dysplasia in NF1- Calorie restriction, sirtuins and bone- Mechanism of cancer bone metastasis