Correspondence
Correction
Serotonin Rising
N Engl J Med 2009; 360:2580-2582June 11, 2009
- Article
To the Editor:
Rosen's Perspective article (March 5 issue)1 highlights recent findings that gut-derived serotonin inhibits bone formation by stimulating serotonin receptors on the preosteoblast.2 A critical question is whether serotonin is delivered to bone in some blood element or as free plasma serotonin. The serum serotonin measurements used by Yadav and colleagues2 reflect an undefined proportion of the platelet pool and say nothing about the minuscule and often mismeasured free plasma concentrations.3
If the platelet is the delivery vehicle, it is paradoxical that increased platelet serotonin levels in Lrp5-knockout animals and patients with osteoporosis pseudoglioma lead to bone loss,2 whereas 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 maternally derived serotonin in mammalian embryogenesis5 poses a similar puzzle: How can gestational SSRI treatment markedly reduce maternal platelet serotonin levels without disrupting embryonic development? Perhaps local tissue uptake and release are crucial in regulating exposures. Finally, given the apparent inhibitory role of serotonin (however delivered) in bone formation,1,2 it is puzzling that the carcinoid syndrome has not been commonly associated with osteoporosis.
5 ReferencesGeorge M. Anderson, Ph.D.
Yale University School of Medicine, New Haven, CT 06520
george.anderson@yale. edu Edwin H. Cook, Jr., M.D.
University of Illinois at Chicago, Chicago, IL 60612Randy D. Blakely, Ph.D.
Vanderbilt University, Nashville, TN 372321
Rosen CJ . Serotonin rising -- the bone, brain, bowel connection. N Engl J Med 2009;360:957-959
Full Text | Web of Science | Medline2
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 | Medline3
Beck O ,Wallen NH ,Broijersen 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 | Medline4
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
CrossRef | Web of Science | Medline5
Cote 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
CrossRef | Web of Science | Medline
To the Editor:
Do carcinoids shed light on serotonin-induced osteoporosis? Yadav et al.1 discovered that duodenal-derived circulating serotonin (whether in platelets or free is unspecified) inhibits bone formation. In his Perspective article, Rosen interprets this finding as an explanation for SSRI-induced osteoporosis. SSRIs significantly reduce circulating serotonin by inhibiting platelet uptake of serotonin as a consequence of blocking the serotonin transporter. Normally, circulating serotonin is almost entirely confined to platelets. We do not know the levels of free serotonin in patients taking SSRIs, but they would be expected to be elevated.
We detected highly elevated levels of serotonin in platelets and free plasma in patients with serotonin-producing metastatic carcinoid tumors, with a median level of free serotonin of 82.1 nmol per liter (as compared with 4.0 nmol per liter among healthy control subjects) and a median level of platelet serotonin of 18.0 nmol per 1×109 platelets, as compared with 3.4 nmol per 1×109 platelets among control subjects.2,3 However, there are no obvious leads pointing to osteoporosis in such patients. Even in cases of bone metastases, we observed no changes in patients' bone-metabolism markers.4
This discrepancy may well be due to the fact that apart from circulating serotonin, metabolic clearance plays a role. Since SSRIs also reduce serotonin clearance in peripheral transporter–expressing target organs, such as bone, serotonin-receptor activation is increased. In contrast, in patients with carcinoid tumors, transporter function is intact, and metabolic clearance can be highly up-regulated.4
4 ReferencesWilhelmina 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@lc. umcg. nl 1
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 | Medline2
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
Web of Science | Medline3
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
Web of Science | Medline4
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 receptor type 1 (CB1) on osteoblasts, nor was this the cause of increased bone formation after traumatic brain injury.1 Rather, they describe CB1 receptors on presynaptic terminals of the sympathetic neurons innervating osteoblasts. The proposed mechanism for increased bone formation was inhibition of norepinephrine release from sympathetic nerve terminals by the endogenous endocannabinoid 2-arachidonoylglycerol.
The β2-adrenergic receptor on the osteoblasts is reported to be the target of this norepinephrine.1,2 It is generally understood that norepinephrine has poor affinity for the β2-adrenergic receptor.3 This suggests two possibilities: either the concentration of norepinephrine in the synapse is sufficiently high to activate β2-adrenergic receptors to cause a response in the osteoblasts or epinephrine that is taken up and recycled by sympathetic nerve terminals4 activates the β2-adrenergic receptors, leading to increased diversion of osteoblasts to osteoclasts.
4 ReferencesRobert C. Speth, Ph.D.
University of Mississippi, University, MS 38677
speth@olemiss.edu 1
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
CrossRef | Web of Science | Medline2
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 | Web of Science | Medline3
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
CrossRef | Web of Science | Medline4
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
CrossRef | Web of Science | Medline
Author/Editor Response
Speth is correct in pointing out an error in my Perspective article in regard to the relationship between CB1 receptors and osteoblast function. In the head-injury model reported by Tam et al., the CB1 receptors were on presynaptic terminals of sympathetic fibers innervating osteoblasts.1 The proposed mechanism for the increase in bone mass in this model was the activation of cannabinoid receptor type 1 by endogenous cannabinoids, leading to the inhibition of norepinephrine release. Nevertheless, this study illustrates our growing understanding of the relationship between neuronal signaling and target cells in the bone marrow that define the rate of bone remodeling. In fact, Olmsted-Davis et al. recently reported that in an animal model of heterotopic ossification induced by bone morphogenetic protein 2, neurons and their progenitor cells appear very early and well before the vascular and osteogenic phases of new bone formation are established.2 With respect to the mechanism of bone loss from sympathetic activity, activated adrenergic receptors on osteoblasts suppress critical transcription factors necessary for bone formation but also enhance osteoclastogenesis, principally by up-regulating the osteoclast differentiation factor RANKL.3 This is not a diversion of osteoblasts to osteoclasts, as noted by Speth, but rather a dynamic process of coupling that involves two cell types originating from distinct progenitor cells.
Anderson and colleagues raise an important question: How does the delivery of circulating serotonin affect bone? Clearly, there are dynamic changes in both platelet uptake and renal clearance, as noted by de Jong et al. in their letter, and these functions 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 on the reuptake of serotonin by the central nervous system.4 Hence, it is conceivable that there is a balance in bone turnover between the central blockade of serotonin reuptake and changes that may be associated with circulating serotonin and its release from platelets. Furthermore, as de Jong et al. state, high serotonin levels in the carcinoid syndrome did not correlate with markers of bone turnover. These data reinforce the need for comprehensive longitudinal studies of circulating serotonin measured in a standardized manner in patients with osteoporosis and other disorders.
4 ReferencesClifford Rosen, M.D.
Maine Medical Center Research Institute, Scarborough, ME 040741
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
CrossRef | Web of Science | Medline2
Olmsted-Davis E ,Gannon FH ,Ozen M , et al. Hypoxic adipocytes pattern early heterotopic bone formation. Am J Pathol 2007;170:620-632
CrossRef | Web of Science | Medline3
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 | Web of Science | Medline4
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
- Citing Articles (4)
Citing Articles
1
George M. Anderson, Margaret E. Hertzig, P. A. McBride. (2011) Brief Report: Platelet-Poor Plasma Serotonin in Autism. Journal of Autism and Developmental Disorders
CrossRef2
Wilhelmina H.A. de Jong, Elisabeth G.E. de Vries, Ido P. Kema. (2011) Current status and future developments of LC-MS/MS in clinical chemistry for quantification of biogenic amines. Clinical Biochemistry 44:1, 95-103
CrossRef3
Massimo Cocchi, Lucio Tonello, Fabio Gabrielli, Massimo Pregnolato. (2011) Depression, osteoporosis, serotonin and cell membrane viscosity between biology and philosophical anthropology. Annals of General Psychiatry 10:1, 9
CrossRef4
Wilhelmina H. A. Jong, Marianne H. L. I. Wilkens, Elisabeth G. E. Vries, Ido P. Kema. (2010) Automated mass spectrometric analysis of urinary and plasma serotonin. Analytical and Bioanalytical Chemistry 396:7, 2609-2616
CrossRef
