Can Serotonin help you Grow Taller?

CH Turner was one of the load researchers behind Lateral Synovial Joint Loading who unfortunately passed away on July 16th,2010 which is likely why there hasn't been much research on LSJL since the groundbreaking study that found LSJL possible to increase limb length. CH. Turner was the main expert on bone research with Hiroki Yokota providing more of the gene expression analysis(mechanotransduction).  CH Turner's most likely successor is the scientist SJ Warden whom I'll be watching for any LSJL related studies.  CH Turner did leave us some artifacts in addition to his LSJL legacy.

One of his last papers was about Serotonin, a neurotransmitter.  Neurotransmitters have had height increase benefits before like with melatonin.  Busiprone stimulates serotonin receptors.

The emerging role of serotonin (5-hydroxytryptamine) in the skeleton and its mediation of the skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5).

"Novel molecular pathways obligatory for bone health are being rapidly identified. One pathway recently revealed involves gut-derived 5-hydroxytryptamine (5-HT) mediation of the complete skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5)[Serotonin helps to mediate some of the skeletal effects of LRP5]. Mounting evidence supports 5-HT as an important regulatory compound in bone with previous evidence demonstrating that bone cells possess functional pathways for responding to 5-HT[Bone cells have receptors for serotonin]. In addition, there is growing evidence that potentiation[potentiation means enhancement] of 5-HT signaling via inhibition of the 5-HT transporter (5-HTT) has significant skeletal effects. The later is clinically significant as the 5-HTT is a popular target of pharmaceutical agents, such as selective serotonin reuptake inhibitors (SSRIs)[So if inhibiting 5-HTT can increase height then SSRIs can increase height as well], used for the management of major depressive disorder and other affective conditions. The observation that 5-HT mediates the complete skeletal effects of LRP5 represents a significant paradigm shift from the traditional view that LRP5 located on the cell surface membrane of osteoblasts exerts direct skeletal effects via Wnt/beta-catenin signaling. This paper discusses the mounting evidence for skeletal effects of 5-HT and the ability of gut-derived 5-HT to satisfactorily explain the skeletal effects of LRP5."

Serotonin interacts with LRP5 to modulate bone cells. There are Serotonin reuptake inhibitors on the market that inhibit the reuptake of Serotonin. Note there are a lot of contradictory studies about Serotonin where some say it stimulates bone and others say it inhibits bone.

"5-HT receptors have been identified in all the major bone cell types (osteoblasts, osteocytes and osteoclasts), and stimulation of these receptors influences bone cell activities"

"Direct stimulatory effect on bone formation pathways with 5-HT increasing prostaglandin E₂ release from osteocyte-like (MLO-Y4) cells and enhancing proliferation of MC3T3-E1 cells and primary human osteoblasts"

"Cells (RAW264.7 and human peripheral blood mononuclear cells stimulated with RANKL) treated with 5-HT (0.01–50 μM) or a SSRI (fluoxetine; 0.001–10 μM) increased their differentiation into osteoclast-like cells and increased their bone-resorption activity"

"Binding of Wnt to its LRP5 and frizzled co-receptors inactivates glycogen synthase kinase-3β (GSK-3β) allowing for cytoplasmic accumulation of β-catenin which subsequently translocates into the nucleus to influence gene transcription "

So LRP5 is another GSK-3B inhibitor.  Bone vibration also inhibits GSK-3Beta.

"The initial motivation leading to the identification of the LRP5–5-HT–osteoblast pathway was to better understand the skeletal role of LRP5. Bones from mice with a loss-of-function mutation in Lrp5 (Lrp5^−/−) exhibited a specific molecular signature of decreased expression of genes associated with cell proliferation, but not osteoblast differentiation, bone matrix deposition, or osteoclast differentiation "

"Lrp5 gain-of-function mutations exhibited significantly increased femoral bone mass, compared to knock-in mice not harboring the Col2.3-Cre transgene."

As for the contradictory statements throughout the study about Serotonin:

"It is possible that 5-HT has both anabolic and catabolic skeletal effects, with the prevailing effect being determined by the extracellular concentration of 5-HT and the respective 5-HT receptor/s activated."

To grow taller it may be better to modulate LRP5 or find other ways to phosphorylate GSK-3Beta.

"The negative skeletal effects of elevated circulating 5-HT also do not explain the negative skeletal effects of SSRIs. Administration of a single-dose of an SSRI (fluoxetine) transiently increases plasma 5-HT levels; however, chronic administration of the same SSRI over 1–2 weeks results in substantial reductions in both whole-blood and plasma 5-HT levels"

So the negative feedback mechanism results in lowered Serotonin levels overall(cycling could help?).

"SSRIs impact the skeleton by directly inhibiting the 5-HTT located on bone cell membranes. This may increase local 5-HT levels, in spite of decreased circulating 5-HT, by reducing its removal from the bone cell microenvironment."

According to Static and cyclic tensile strain induce myxomatous effector proteins and serotonin in canine mitral valves, static and cyclic tensile strain can induce both serotonin and chondrogenic factors.

Serotonin acts as a receptor for LRP5 which is a GSK-3Beta inhibitor. Even though this study was on bone cells, inhibiting GSK-3Beta has been shown to increase height in chondrocytes.  Inhibition of GSK-3Beta results in enhanced hypertrophic differentiation of chondrocytes.  Unfortunately, there are no direct studies on Serotonin and chondrocytes. Serotonin and Fluoxetine do have the potential to increase height but care has to be involved in terms of addressing the negative feedback mechanisms. Alternatively, other ways of phosphorylating GSK-3Beta can be found or methods to modify LRP5 directly.


Inactivation of Lrp5 in Osetocytes Reduces Young's Modulus and Responsiveness to the Mechanical Loading.

"Low-density-lipoprotein receptor-related protein 5 (Lrp5) is a co-receptor in Wnt signaling, which plays a critical role in development and maintenance of bone. Osteoporosis-pseudoglioma syndrome, for instance, arises from loss-of- function mutations in Lrp5, and global deletion of Lrp5 in mice results in significantly lower bone mineral density. Since osteocytes are proposed to act as a mechanosensor in bone, we addressed a question whether a conditional loss-of-function mutation of Lrp5 selective to osteocytes (Dmp1-Cre; Lrp5(f/f)) would alter responses to ulna loading. Loading was applied [AXIALLY to the right ulna for 3 min (360 cycles at 2 Hz) at a peak force of 2.65 N for 3 consecutive days, and the contralateral ulna was used as a non-loaded control. Young's modulus was determined using a midshaft section of the femur. Compared to age-matched littermate controls, mice lacking Lrp5 in osteocytes exhibited smaller skeletal size with reduced bone mineral density and content. Compared to controls, Lrp5 deletion in osteocytes also led to a 4.6-fold reduction in Young's modulus. In response to ulna loading, mineralizing surface, mineral apposition rate, and bone formation rate were diminished in mice lacking Lrp5 in osteocytes by 52%, 85%, and 69%, respectively.  Loss-of-function mutation of Lrp5 in osteocytes causes suppression of mechanoresponsiveness and reduces bone mass and Young's modulus. Lrp5-mediated Wnt signaling significantly contributes to maintenance of mechanical properties and bone mass."

16-week old mice were used.  Bone images were taken 18 days after the first of three consecutive days in which axial loading was performed.

"the strain gauge was mounted on the lateral face of the ulna, approximately 100 m from the neutral bending axis of the bone"

Osteocyte-specific KO of LRP5 had reduced femoral bone and spinal bone length.

"In response to [a] bout of cyclic loads, the ulna of the KO mice showed significantly higher strain (3,762 ± 69.6 ) than the littermate control mice (703 ± 34.6 )"

"Periosteal mineralizing surface was significantly reduced [in response to LSJL ulnar loading] in the KO mice (31.6 ± 3.1% in control, and 15.2 ± 7.1% in KO).  mineral apposition rate was decreased significantly (0.74 ± 0.15 m/day in control, and 0.11 ± 0.12 m/day in KO)"

"Both global and conditional inactivation of Lrp5 show low bone mass and decreased bone strength. The anabolic response to ulna loading was reduced by ~94% (global KO) and ~78% (conditional KO in this study)."