Grow Larger with Histamines?

A histamine is a neurotransmitter that triggers the inflammatory response.  Histamines may play a role in increasing chondrocyte proliferation and may thereby encourage height growth.

Accelerated Ca2+ entry by membrane hyperpolarization due to Ca2+-activated K+ channel activation in response to histamine in chondrocytes.

"histamine release from mast cells can enhance cytokine production and matrix synthesis and also promote cell proliferation by stimulating chondrocytes[Remember our goal is to increase hydrostatic pressure and interstitial fluid flow to induce stem cells to differentiate into chondrocytes]. In this study, the functional impact of Ca(2+)-activated K(+) (K(Ca)) channels in the regulation of intracellular Ca(2+) concentration ([Ca(2+)](i)) in chondrocytes in response to histamine was examined using OUMS-27 cells, as a model of chondrocytes derived from human chondrosarcoma. Application of histamine induced a significant [Ca(2+)](i) rise[remember intracellular calcium secretions can induce chondrogenesis] and also membrane hyperpolarization, and both effects were mediated by the stimulation of H(1) receptors. The histamine-induced membrane hyperpolarization was attenuated to approximately 50% by large-conductance K(Ca) (BK) channel blockers, and further reduced by intermediate (IK) and small conductance K(Ca) (SK) channel blockers. The tonic component of histamine-induced [Ca(2+)](i) rise strongly depended on the presence of extracellular Ca(2+) ([Ca(2+)](o)) and was markedly reduced by La(3+) or Gd(3+) but not by nifedipine. It was significantly attenuated by BK channel blockers, and further blocked by the cocktail of BK, IK, and SK channel blockers. The K(Ca) blocker cocktail also significantly reduced the store-operated Ca(2+) entry (SOCE), which was induced by Ca(2+) addition after store-depletion by thapsigargin in [Ca(2+)](o) free solution. Our results demonstrate that the histamine-induced membrane hyperpolarization in chondrocytes due to K(Ca) channel activation contributes to sustained Ca(2+) entry mainly through SOCE channels in OUMS-27 cells. Thus, K(Ca) channels appear to play an important role in the positive feedback mechanism of [Ca(2+)](i) regulation in chondrocytes in the presence of articular cartilage inflammation."

"the tonic phase may be mainly due to sustained Ca2+ entry through Ca2+-permeable ion channels rather than L-type voltage-gated Ca2+ channels."<-we would rather have the channels

Histamine increased calcium uptake by chondrocytes.  If it does the same thing to stem cells it could possibly induce mesenchymal stem cell chondrogenesis.

Histamine stimulates the proliferation of human articular chondrocytes in vitro and is expressed by chondrocytes in osteoarthritic cartilage.

"HAC in vitro were incubated with and without histamine in 96 well culture plates and the extent of cell proliferation was determined using the naphthol blue-black method. Histamine effects were analysed with the histamine H(1) and H(2) receptor antagonists, mepyramine and ranitidine, respectively. Rabbit polyclonal antibodies and alkaline phosphatase conjugated secondary antibodies were used, and histamine and HDC were demonstrated by immunohistochemistry in OA cartilage tissues.
Histamine stimulated the proliferation of HAC in culture. This stimulation was blocked by the addition of mepyramine, but not ranitidine, suggesting that the effect is mediated through H(1) histamine receptors. The addition of alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase (the enzyme responsible for histamine production), reduced the rate of proliferation of HAC. Both histamine and histidine decarboxylase were demonstrated in chondrocytes of OA cartilage by immunohistochemistry.
Changes induced by histamine in the proliferative rate of HAC may contribute to the formation of chondrocyte clusters associated with OA cartilage; an observation supported by the demonstration of histamine and HDC expression by chondrocytes of OA cartilage in situ."

"H1 and H2 histamine receptors are expressed by human articular chondrocytes (HAC); stimulation of the H1 receptors resulted in increased prostaglandin E2 (PGE2) production, whereas stimulation of the H2 receptors resulted in increased cAMP."

"histamine stimulates the production of matrix metalloproteinases (MMPs)-13 and -3 (collagenase 3 and stromelysin-1, respectively) by HAC in vitro"

The optimal histamine dosage for chondrocyte proliferation was 50 micromol's per liter but there was not much difference between 20 and 100 in terms of proliferation giving a reasonable margin of error in histamine dose.

Histamine 4-receptor may be involved in chondrocyte hypertrophy:


Increased expression of the histamine H4 receptor subtype in hypertrophic differentiation of chondrogenic ATDC5 cells.

"The expression of histamine H(4) receptor (H(4)R) mRNA in synovial tissues was significantly higher in patients with osteoarthritis (OA) compared to those with rheumatoid arthritis. Chondrocyte hypertrophy and endochondral ossification are essential processes in pathologic disorders such as osteophyte formation during OA progression. In the present study, we examined the expression of H(4) R during differentiation into hypertrophic chondrocytes in the ATDC5 cells, a widely used in vitro model of chondrogenic differentiation. Quantitative reverse transcription polymerase chain reaction showed that the levels of histidine decarboxylase and H(4)R mRNA on ATDC5 cells were increased in a time-dependent manner during the culture period. By contrast, the expressions of H(1)R and H(2)R were not increased from day 7 onwards. The mRNA expression of the hypertrophic chondrocyte marker type X collagen (COL X) was increased markedly from 14 to 21. Immunocytochemical analysis indicated that H(4)R staining was strongly immunoreactive on the plasma membrane of ATDC5 cells. Flow cytometry showed increased expression of H(4)R and COL X protein in ATDC5 chondrocytes. Furthermore, the majority of the COL X-positive cells expressed H(4) R throughout the culture period. In summary, we showed for the first time that H(4)R is expressed in ATDC5 chondrocytes. Moreover, we found that most hypertrophic chondrocytes express H(4)R, suggesting that this receptor might be associated with the differentiation of chondrocytes into hypertrophic cells"

"[bone marrow expresses H4R]"

Osteoarthiritis is very important to height increase studies because osteoarthiritic cartilage is cartilage that undergoes endochondral ossificatio.  Maybe this is partly responsible for the pockets of bone that occurred in epiphyseal distraction in the hyaline cartilage growth plate line(histamine resulted in chondrocytes to undergo endochondral ossification in the hyaline cartilage growth plate line).  Now this is not necessarily bad as despite the pockets of bone the hyaline cartilage line was still there and functional.

So histamine has potential height increasing effects but it also has potentially undesirable effects like endochondral ossification in articular cartilage and the creation of bony artifacts in the hyaline cartilage.  Note in the LSJL histology there were no bony artifacts in contrast to epiphyseal distraction.