Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: evidence from in vitro and animal-based studies

Abstract

The regulation of bone metabolism continues to be an area of intense investigation, with recent evidence indicating a potential contribution from the neural system. In particular, the neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) has been hypothesized to play a role in skeletal metabolism via its transporter (5-HTT). The 5-HTT is a plasma membrane transporter that is highly specific for the uptake of extracellular 5-HT, thereby facilitating the intracellular storage and/or degradation of 5-HT. The 5-HTT is clinically important as it is the key target of pharmaceutical agents aimed at treating affective disorders, such as major depressive disorder. By antagonizing the 5-HTT, selective serotonin reuptake inhibitors (SSRIs) potentiate 5-HT activity and effectively relieve the symptoms of depression. However, questions have been raised regarding the potential skeletal effects of SSRIs given the recent identification of a functional 5-HTT and functional 5-HT receptors in bone cells. This paper discusses the preclinical evidence for the skeletal effects of 5-HT and the inhibition of the 5-HTT. In particular, it discusses the: (1) role of 5-HT and the function of the 5-HTT; (2) presence of functional 5-HTTs in bone; (3) potential sources and response mechanisms for 5-HT in bone, and; (4) in vitro and in vivo skeletal effects of 5-HT and 5-HTT inhibition.

Figure 1

(A) 5-hydroxytryptamine (5-HT) transmission within the central nervous system and (B) the effects of 5-HT transporter (5-HTT) inhibition. (i) 5-HT is manufactured by presynaptic neurons and stored in vesicles. (ii) Vesicles bind with the cell membrane following an appropriate stimulus to release 5-HT into the syntapic cleft via exocytosis. (iii) Released 5-HT activates post-synaptic receptors to stimulate the post-synaptic neuron. (iv) Membrane-bound serotonin transporters (5-HTT) uptake released 5-HT to control the duration of 5-HT effects and recycle or degrade 5-HT. (v) Inhibition of the 5-HTT (i.e. by the administration of a selective serotonin reuptake inhibitor) prevents uptake of 5-HT from resulting in its accumulation within the synaptic cleft and prolonging of its effects.

Figure 2

Potential sources of 5-HT in the skeleton. Indirect sources include 5-HT derived from the central nervous system, gastrointenstinal tract and cardiovascular system. Direct sources include the possible synthesis of 5-HT by bone cells themselves, in which case skeletal 5-HT effects may be autocrine/paracrine in nature (Reprinted from Warden SJ, et al. Neural regulation of bone and the skeletal effects of serotonin (5-hydroxytryptamine). Mol Cell Endocrinol 2005;242:1-9, with permission from Elsevier).

Figure 3

Biosynthesis of 5-HT from tryptophan. Tryptophan hydroxylation is the first and rate-limiting step. The enzyme responsible for this step (tryptophan hydroxylase) has been identified in all of the major bone cell types (osteoblasts, osteocytes and osteoclasts) suggesting that each may be capable of synthesizing 5-HT.