To the Editor: Rosen's Perspective article (March 5 issue)1highlights recent findings that gut-derived serotonin inhibitsbone formation by stimulating serotonin receptors on the preosteoblast.2A critical question is whether serotonin is delivered to bonein some blood element or as free plasma serotonin. The serumserotonin measurements used by Yadav and colleagues2 reflectan undefined proportion of the platelet pool and say nothingabout the minuscule and often mismeasured free plasma concentrations.3
If the platelet is the delivery vehicle, it is paradoxical thatincreased platelet serotonin levels in Lrp5-knockout animalsand patients with osteoporosis pseudoglioma lead to bone loss,2whereas treatment with selective serotonin-reuptake inhibitors(SSRIs), which lowers platelet serotonin levels by 80 to 95%,also reduces bone mass.4 The apparent requirement for maternallyderived serotonin in mammalian embryogenesis5 poses a similarpuzzle: How can gestational SSRI treatment markedly reduce maternalplatelet serotonin levels without disrupting embryonic development?Perhaps local tissue uptake and release are crucial in regulatingexposures. Finally, given the apparent inhibitory role of serotonin(however delivered) in bone formation,1,2 it is puzzling thatthe carcinoid syndrome has not been commonly associated withosteoporosis.
George M. Anderson, Ph.D. Yale University School of Medicine New Haven, CT 06520 george.anderson{at}yale.edu
Edwin H. Cook, Jr., M.D. University of Illinois at Chicago Chicago, IL 60612
Randy D. Blakely, Ph.D. Vanderbilt University Nashville, TN 37232
References
Rosen CJ. Serotonin rising -- the bone, brain, bowel connection. N Engl J Med 2009;360:957-959. [Free Full Text]
Yadav VK, Ryu JH, Suda N, et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 2008;135:825-837. [CrossRef][Web of Science][Medline]
Beck O, Wallén NH, Bröijersén A, Larsson PT, Hjemdahl P. On the accurate determination of serotonin in human plasma. Biochem Biophys Res Commun 1993;196:260-266. [CrossRef][Web of Science][Medline]
Diem SJ, Blackwell TL, Stone KL, et al. Use of antidepressants and rates of hip bone loss in older women: the Study of Osteoporotic Fractures. Arch Intern Med 2007;167:1240-1245. [Free Full Text]
Côté F, Fligny C, Bayard E, et al. Maternal serotonin is crucial for murine embryonic development. Proc Natl Acad Sci U S A 2007;104:329-334. [Free Full Text]
To the Editor: Do carcinoids shed light on serotonin-inducedosteoporosis? Yadav et al.1 discovered that duodenal-derivedcirculating serotonin (whether in platelets or free is unspecified)inhibits bone formation. In his Perspective article, Rosen interpretsthis finding as an explanation for SSRI-induced osteoporosis.SSRIs significantly reduce circulating serotonin by inhibitingplatelet uptake of serotonin as a consequence of blocking theserotonin transporter. Normally, circulating serotonin is almostentirely confined to platelets. We do not know the levels offree serotonin in patients taking SSRIs, but they would be expectedto be elevated.
We detected highly elevated levels of serotonin in plateletsand free plasma in patients with serotonin-producing metastaticcarcinoid tumors, with a median level of free serotonin of 82.1nmol per liter (as compared with 4.0 nmol per liter among healthycontrol subjects) and a median level of platelet serotonin of18.0 nmol per 1x109 platelets, as compared with 3.4 nmol per1x109 platelets among control subjects.2,3 However, there areno obvious leads pointing to osteoporosis in such patients.Even in cases of bone metastases, we observed no changes inpatients' bone-metabolism markers.4
This discrepancy may well be due to the fact that apart fromcirculating serotonin, metabolic clearance plays a role. SinceSSRIs also reduce serotonin clearance in peripheral transporter–expressingtarget organs, such as bone, serotonin-receptor activation isincreased. In contrast, in patients with carcinoid tumors, transporterfunction is intact, and metabolic clearance can be highly up-regulated.4
Wilhelmina H.A. de Jong, M.S. Elisabeth G.E. de Vries, M.D.,Ph.D. Ido P. Kema, Ph.D. University Medical Center Groningen 9700 RB Groningen, the Netherlands i.p.kema{at}lc.umcg.nl
References
Yadav VK, Ryu JH, Suda N, et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 2008;135:825-837. [CrossRef][Web of Science][Medline]
Kema IP, de Vries EG, Schellings AM, Postmus PE, Muskiet FA. Improved diagnosis of carcinoid tumors by measurement of platelet serotonin. Clin Chem 1992;38:534-540. [Free Full Text]
Meijer WG, van der Veer E, Jager PL, et al. Bone metastases in carcinoid tumors: clinical features, imaging characteristics, and markers of bone metabolism. J Nucl Med 2003;44:184-191. [Free Full Text]
Gillis CN. Peripheral metabolism of serotonin. In: Vanhoutte PM, ed. Serotonin and the cardiovascular system. New York: Raven Press, 1985:27-36.
To the Editor: The article by Rosen contains a minor error.Tam et al. did not report the presence of cannabinoid receptortype 1 (CB1) on osteoblasts, nor was this the cause of increasedbone formation after traumatic brain injury.1 Rather, they describeCB1 receptors on presynaptic terminals of the sympathetic neuronsinnervating osteoblasts. The proposed mechanism for increasedbone formation was inhibition of norepinephrine release fromsympathetic nerve terminals by the endogenous endocannabinoid2-arachidonoylglycerol.
The β2-adrenergic receptor on the osteoblasts is reportedto be the target of this norepinephrine.1,2 It is generallyunderstood that norepinephrine has poor affinity for the β2-adrenergicreceptor.3 This suggests two possibilities: either the concentrationof norepinephrine in the synapse is sufficiently high to activateβ2-adrenergic receptors to cause a response in the osteoblastsor epinephrine that is taken up and recycled by sympatheticnerve terminals4 activates the β2-adrenergic receptors,leading to increased diversion of osteoblasts to osteoclasts.
Robert C. Speth, Ph.D. University of Mississippi University, MS 38677 speth{at}olemiss.edu
References
Tam J, Trembovler V, Di Marzo V, et al. The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling. FASEB J 2008;22:285-294. [Free Full Text]
Elefteriou F, Ahn JD, Takeda S, et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 2005;434:514-520. [CrossRef][Medline]
Hoffmann C, Leitz MR, Oberdorf-Maass S, Lohse MJ, Klotz KN. Comparative pharmacology of human beta-adrenergic receptor subtypes -- characterization of stably transfected receptors in CHO cells. Naunyn Schmiedebergs Arch Pharmacol 2004;369:151-159. [Web of Science][Medline]
Lameris TW, de Zeeuw S, Duncker DJ, et al. Epinephrine in the heart: uptake and release, but no facilitation of norepinephrine release. Circulation 2002;106:860-865. [Free Full Text]
The author replies: Speth is correct in pointing out an errorin my Perspective article in regard to the relationship betweenCB1 receptors and osteoblast function. In the head-injury modelreported by Tam et al., the CB1 receptors were on presynapticterminals of sympathetic fibers innervating osteoblasts.1 Theproposed mechanism for the increase in bone mass in this modelwas the activation of cannabinoid receptor type 1 by endogenouscannabinoids, leading to the inhibition of norepinephrine release.Nevertheless, this study illustrates our growing understandingof the relationship between neuronal signaling and target cellsin the bone marrow that define the rate of bone remodeling.In fact, Olmsted-Davis et al. recently reported that in an animalmodel of heterotopic ossification induced by bone morphogeneticprotein 2, neurons and their progenitor cells appear very earlyand well before the vascular and osteogenic phases of new boneformation are established.2 With respect to the mechanism ofbone loss from sympathetic activity, activated adrenergic receptorson osteoblasts suppress critical transcription factors necessaryfor bone formation but also enhance osteoclastogenesis, principallyby up-regulating the osteoclast differentiation factor RANKL.3This is not a diversion of osteoblasts to osteoclasts, as notedby Speth, but rather a dynamic process of coupling that involvestwo cell types originating from distinct progenitor cells.
Anderson and colleagues raise an important question: How doesthe delivery of circulating serotonin affect bone? Clearly,there are dynamic changes in both platelet uptake and renalclearance, as noted by de Jong et al. in their letter, and thesefunctions are significantly altered in patients receiving SSRIs.In my article, I point out that the article by Yadav et al.did not elucidate the mechanism of bone loss with these agents,particularly since this drug class has a profound effect onthe reuptake of serotonin by the central nervous system.4 Hence,it is conceivable that there is a balance in bone turnover betweenthe central blockade of serotonin reuptake and changes thatmay be associated with circulating serotonin and its releasefrom platelets. Furthermore, as de Jong et al. state, high serotoninlevels in the carcinoid syndrome did not correlate with markersof bone turnover. These data reinforce the need for comprehensivelongitudinal studies of circulating serotonin measured in astandardized manner in patients with osteoporosis and otherdisorders.
Clifford Rosen, M.D. Maine Medical Center Research Institute Scarborough, ME 04074
References
Tam J, Trembovler V, Di Marzo V, et al. The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling. FASEB J 2008;22:285-294. [Free Full Text]
Olmsted-Davis E, Gannon FH, Ozen M, et al. Hypoxic adipocytes pattern early heterotopic bone formation. Am J Pathol 2007;170:620-632. [Free Full Text]
Elefteriou F, Ahn JD, Takeda S, et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 2005;434:514-520. [CrossRef][Medline]
Yadav VK, Ryu JH, Suda N, et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 2008;135:825-837. [CrossRef][Web of Science][Medline]
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