Serotonin i BBB Conection

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n engl j med 360;10 nejm.org march 5, 2009

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In a recent article, Yadav et al.1

elucidated the regulation of gut-produced serotonin by low-density

lipoprotein receptorrelated pro-tein 5 (Lrp5) and the deleteriouseffect of serotonin on bone mass.This discovery reflects the rapidadvances taking place in bone bi-ology and lends support to threenewly understood facts about skel-etal physiology.

The first fact relates to the pre-eminence, in skeletal acquisitionand maintenance, of a signalingpathway consisting of the mam-

malian homologue of wingless indrosophila (Wnt), Lrp5 or Lrp 6,and -catenin. This pathways im-portance was firmly establishedthrough clinical observations fromgain-of-function and loss-of-func-tion mutations in the LRP5gene,genetically engineered mouse mod-els of WntLrp components, andin vitro studies of this signalingnetwork in osteoblasts. The sec-ond fact is the importance of adi-pose tissue in modulating boneturnover. Studies in mice have es-tablished that leptin, an adipokinesecreted from peripheral fat de-pots, plays a prominent role inbone formation by activating sym-pathetic signals through a hypo-thalamic relay, rather than throughendocrine or paracrine pathwaysin the skeleton. The third and mostprovocative new concept is that

the brain can have an importantinfluence on the process of skel-etal remodeling.

Although not all the mecha-nisms operative in the bonebrainconnection have been defined,clinical observations suggest thatthis link may be very important.For example, after traumatic brain

injury, the rate of new bone for-mation can suddenly and rapidlyincrease. Conversely, several stud-

ies have suggested that clinical de-pression may be associated withlow bone mass. And most recently,two large cohort studies revealedthat the use of selective serotonin-reuptake inhibitors (SSRIs), theclass of drugs most frequentlyprescribed for depression, is as-sociated with twice the annualrate of bone loss that occurs witholder tricyclic antidepressants.2

How does the brain influence

osteoblastic activity and regulatebone remodeling? Three mecha-nisms are plausible. First, in ex-perimental states of bone forma-tion, neural stem cells are earlyand critical components in theprocess of angiogenesis and osteo-blastic recruitment. Second, thereis strong evidence that there are-adrenergic receptors on osteo-blasts and that enhanced sym-pathetic activity can trigger thesereceptors to suppress bone forma-tion and cause bone loss. Third,several groups have demonstratedthe presence of neurotransmitterreceptors on osteoblasts. These in-clude the cannabinoid receptortype 1 and the family of neuro-peptide Y (NPY) receptors (Y1through Y5). In a recent study,Tam et al. demonstrated that theincreased bone formation seen

after traumatic brain injury wasmediated by the cannabinoid re-ceptor on osteoblasts.3 Anotherneurotransmitter is NPY, whichis an important hypothalamic me-diator of appetite. NPY fibers havealso been found in the bone mar-row and periosteum, and severalstudies suggest that Y1 receptors

in the osteoblast mediate the ef-fects of NPY on bone remodeling.4Serotonin (5-hydroxytryptophan,

or 5-HT) is another neurotrans-mitter with abundant receptors inbone and brain; recent efforts havefocused on delineating its impor-tance for skeletal acquisition andmaintenance.

The physiological actions ofserotonin are unique because ofserotonins ubiquitous nature asa neurotransmitter and its potenteffects on target tissues. Mostcirculating serotonin arises from

synthesis in the duodenum byspecialized neuroendocrine entero-chromaffin cells. The life cycle ofserotonin begins with meal-inducedmucosal stimulation of the gut,which increases the enzymatic ac-tivity of tryptophan hydroxylase(Tph) 1, leading to serotonin syn-thesis (see diagram). Serotoninis then released locally to stimu-late intestinal peristalsis, as wellas to enter the circulation, whereit is taken up by platelets by meansof the specialized 5-HT membranetransporter 5-HTT. Platelets caneither store serotonin or releaseit during the clotting process toenhance vascular constriction andplatelet aggregation.

In the central nervous system,serotonin synthesis is catalyzed byTph2 (see diagram). It is releasedat neural synapses, and its reuptake

is controlled by 5-HTT. Circulat-ing serotonin does not cross thebloodbrain barrier, so all its ac-tivity in the brain is mediated bysynthesis, reuptake, and bindingto a 5-HT receptor (Htr), of whichthere are several, within the cen-tral nervous system. Heritable oracquired variations in the molec-

Serotonin Rising The Bone, Brain, Bowel Connection

Serotonin Rising The Bone, Brain, Bowel ConnectionClifford J. Rosen, M.D.

Copyright 2009 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org by JOAN LLEVADOT MD on March 9, 2009 .


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ular structure or function of Tph2,members of the Htr family, or5-HTT lead to changes in sero-tonin levels in the central nervoussystem, which are thought to beresponsible for depressive and af-fective disorders. Pharmacologicinhibition of 5-HTT by SSRIs

enhances serotonin activity, andthese agents have become extreme-ly popular for treating several psy-chiatric disorders, including de-pression.

Previous efforts to study theeffects of serotonin on bone cellshad mixed results. The experi-

ments centered on modifying5-HTT or an Htr, primarily be-cause experimental evidence hadidentified these proteins in os-teoblasts and osteoclasts. In somestudies in animals, pharmacolog-ic impairment of 5-HTT activity

or deletion of the gene encodingthe Htr2b receptor resulted in highbone mass, whereas in other stud-ies, deletion of the 5-HTT gene de-letion was associated with very lowbone mass that was independentof estrogen deficiency.5The lat-ter findings were consistent withthose from prospective cohortstudies, in which both male andfemale patients who took SSRIslost bone mass.2

Yadav et al. approached thisexperimental paradox in a differ-ent manner, focusing their effortson the relationship of -catenin,the intracellular signaling mole-cule for Lrp5, to serotonin me-tabolism.1It had previously beenestablished that deletion of theLrp5gene led to a profound reduc-tion in histomorphometric mark-ers of bone formation. What wasperplexing to investigators wasthat if -catenin, the canonicalsignaling node for Lrp5, was de-leted only in osteoblasts, there wasno effect on bone formation. Thissurprising finding caused Yadavet al. to look beyond bone for asite where Lrp5 was modulatedand for a mechanism for thatregulation. They found it in themost unlikely of places theduodenum.

In severely osteoporotic Lrp5/

mice, very high levels of Tph1 ex-pression were found in the entero-chromaffin cells, and when thisgene was deleted only in the in-testine, the bone mass of theseLrp5/ mice was fully restored.Yadav et al. then demonstratedthat circulating levels of seroto-


Brain

Serotonin Tph2

Synapse

Serotonin

Serotonin

5-HTT

5-HTT SSRIs

SSRIs

SNS

Bone

Enterochromaffin cell

Platelet

Pre-osteoblast

Osteoblast

Pre-osteoclast

Osteoclast

CREB

Proliferation

Bone resorptionBone formation

HTR1BLrp5

Tph1

Small intestine

Mucosal

stimulation

Serotonin

Serotonin

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Physiological Actions of Serotonin Synthesis, Transport, Reuptake, and Receptor Activation in the Mouse.

Yadav et al.1demonstrated that serotonin in the gut inhibited bone formation by means of thecirculation, completely independently of serotonin activity in the brain. The term 5-HTT denotes

the 5-hydroxytryptamine (5-HT) membrane transporter, CREB cyclic AMP response element-bind-ing protein, Htr1b 5-HT receptor 1b, Lrp5 low-density lipoprotein receptorrelated protein 5, SNS

sympathetic nervous system, SSRI selective serotonin-reuptake inhibitor, and Tph tryptophan hy-droxylase (1 and 2).



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nin suppressed osteoblast prolif-eration by binding to the Htr1bserotonin receptor in bone. Mostintriguingly, several patients withthe rare genetic disorder osteopo-rosis pseudoglioma, a severe os-teoporotic syndrome in children

that results from a loss-of-func-tion mutation in Lrp5, had highlevels of circulating serotonin.

These data provide new per-spectives and new opportunitiesfor researchers and clinicians. Cer-tainly they have caused us to re-think the skeleton as a tissue andits integration with the brain andgut. Second, studies are now un-der way to measure circulating lev-els of serotonin in individual pa-

tients and large cohorts of subjectswho have postmenopausal osteo-porosis to determine whether se-rotonin could be a marker of dis-

ease status. Third, the study byYadav et al. has pushed SSRIsback into the spotlight and willprobably energize investigators toexamine the mechanism of boneloss from these agents and thepotential for pharmacologically

manipulating the 5-HTT systemso that the primary effect of theSSRIs will be limited to the cen-tral nervous system. Finally, theremay be an opportunity to designor modify existing drugs that in-hibit Tph1 activity in the duode-num in the hope of enhancingbone mass. These outcomes andothers raise the profile of seroto-nin and reinforce the thesis thatthere is a connection among bone,

brain, and bowel.Dr. Rosen reports receiving research

grant support from Takeda Pharmaceuti-cals. No other potential conflict of interestrelevant to this art icle was reported.

Dr. Rosen is a senior scientist at the MaineMedical Center Research Institute, Scar-borough.

Yadav VK, Ryu JH, Suda N, et al. Lrp5 con-1.trols bone formation by inhibiting serotoninsynthesis in the duodenum. Cell 2008;135:825-37.

Haney EM, Warden SJ. Skeletal effects of2.

serotonin (5-hydroxytryptamine) transporterinhibition: evidence from clinical studies.J Musculoskelet Neuronal Interact 2008;8:133-45.

Tam J, Trembovler V, Di Marzo V, et al.3.The cannabinoid CB1 receptor regulatesbone formation by modulating adrenergicsignaling. FASEB J 2008;22:285-94.

Rosen CJ. Bone remodeling, energy me-4.tabolism, and the molecular clock. Cell Me-tab 2008;7:7-10.

Warden SJ, Nelson IR, Fuchs RK, Bliziotes5.MM, Turner CH. Serotonin (5-hydroxytrypta-mine) transporter inhibition causes boneloss in adult mice independently of estrogendeficiency. Menopause 2008;15:1176-83.

Copyright 2009 Massachusetts Medical Society.


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