Add some inches to your height with lactoferrin?

Lactoferrin was recently mentioned on the grow tall forum as a possible mechanism in which height can be increased.  Lactoferrin is present in milk making milk doubly attractive due it's ability to also increase circulating levels of IGF-1.  Even though Lactoferrin is present in milk it's possible that additional supplemental Lactoferrin may increase height further.

Inhibitory effect of lactoferrin on hypertrophic differentiation of ATDC5 mouse chondroprogenitor cells.

"The skeleton is formed by two different mechanisms. In intramembranous ossification, osteoblasts form bone directly, whereas in endochondral ossification, chondrocytes develop a cartilage template, prior to osteoblast-mediated skeletogenesis[both osteoblasts and chondrocytes have the ability to add inches to your height]. Lactoferrin is an iron-binding glycoprotein belonging to the transferrin family. It is known to promote the growth and differentiation of osteoblasts. In this study, we investigated the effects of bovine lactoferrin on the chondrogenic differentiation of ATDC5 chondroprogenitor cells. This mouse embryonic carcinoma-derived clonal cell line provides an in vitro model of chondrogenesis. Lactoferrin treatment of differentiating ATDC5 cells promoted cell proliferation in the initial stage of the differentiation process[So Lactoferrin increases chondrocyte proliferation]. However, lactoferrin treatment resulted in inhibition of hypertrophic differentiation, characterized by suppression of alkaline phosphatase activity[although it's mostly methylation status that affects terminal differentiation and not alkaline phosphatase activity], aggrecan synthesis and N-cadherin expression. This inhibitory effect was accompanied by sustained Sox9 expression, as well as increased Smad2/3 expression and phosphorylation, suggesting that lactoferrin regulates chondrogenic differentiation by up-regulating the Smad2/3-Sox9 signaling pathway[Smad 2/3 phosphorylation is the good kind]."

So lactoferrin could potentially increase height by inhibiting chondrogenic hypertrophic differentiation and keeping chondrocytes in the proliferating phase longer.  You need the chondrocytes to undergo hypertrophic differentiation eventually but what Lactoferrin can do is allow for each chondrocyte to maximally proliferate before undergoing hypertrophy.

"Chondrogenic differentiation is characterized by drastic changes in cell shape, which results in the conversion of a flattened shape to a round or polygonal morphology. Rho GTPase acts as a cell shape regulator by controlling organization, polymerization and de-polymerization of actin stress fibers in chondrocytes, as well as other types of cells. Activated (GTP-bound) RhoA stabilizes actin stress fibers by up-regulating both RhoA kinase (ROCK) and LIM kinase. It has been shown that over-expression of RhoA enhances cell proliferation and inhibits hypertrophic differentiation of ATDC5 cells, while inhibition of ROCK activity results in promotion of hypertrophic differentiation. Thus, RhoA/ROCK signaling inhibits the hypertrophic differentiation of chondrocytes, while promoting the proliferation and initial stage of chondrogenic differentiation. Data from our laboratory demonstrate that lactoferrin enhances collagen gel contractile activity in human fibroblasts by activating Rho and MLCK[Lactoferrin activates Rho activity, although this may be a bad thing as MLCK inhibition has been shown to induce chondrogenesis], which suggests that RhoA/ROCK may be involved in lactoferrin-mediated inhibition of hypertrophic differentiation in ATDC5 cells"<-Now the problem with RhoA is that the formation of actin stress fibers seems to be a cause of chondrogenic de-differentiation.  Thus, too much Lactoferrin may have negative effects on height growth.  But Lactoferrin up to a point may be a great boon for height growth.

"Mesenchymal cells undergo chondrogenic differentiation through a cellular condensation stage. N-cadherin is a calcium-dependent cell adhesion molecule that is required for both pre-cartilage condensation and cartilage nodule formation during chondrogenic differentiation[So not being deficient in calcium is important for height growth]. Inhibition of N-cadherin-mediated cell adhesion results in abrogation of cell condensation and subsequent chondrogenesis[without cellular condensation, there is no chondrogenesis.  The compression of the epiphysis during LSJL helps induce this cellular condensation by reducing the space available]. Here, we observed that lactoferrin antagonized N-cadherin expression in differentiating ATDC5 cells. Although Sox9 was reported to bind specifically to an N-cadherin gene promoter region and to increase the transcription and translation of N-cadherin, Sox9 is not essential for N-cadherin expression in vivo[The negative effects of Lactoferrin on cellular condensation may be counteracted by the increase in Sox9 activity]. This finding suggests that in addition to Sox9, it is possible that lactoferrin controls the expression of other genes required for N-cadherin expression."

Signal transduction and metabolism in chondrocytes is modulated by lactoferrin.

"Activation of granulocytes causes a considerable rise in the concentration of lactoferrin (Lf) in synovial fluid (SF).
Signal transduction was analysed in cultured chondrocytes by immunodetection of mitogen activated protein kinases (MAPK) and analysis of Smad2 translocation to the nucleus. Expression levels of matrix metalloproteinases (MMPs) and of aggrecan were measured by reverse-transcription-PCR. The proteolytic activity of MMPs was ascertained by zymography. Expression of the low-density-lipoprotein-receptor-related-protein-1 (LRP-1), a Lf receptor for signalling, was assayed by immunohistochemistry in cartilage and in cultured chondrocytes by immunoblotting.
We found LRP-1 expressed in dedifferentiated chondrocytes in culture and in cartilage tissue preferentially on the articular surface where it can encounter Lf within SF. Lf stimulated proliferation of chondrocytes, comparable to transforming growth factor-beta1 (TGFbeta1) and activated p38 and the extracellular-signal regulated-kinases 1/2 (ERK1/2) within minutes. Surprisingly, Lf induced nuclear Smad2 translocation, a signal pathway ascribed to TGFbeta receptor activation. Lf significantly increased the levels of catabolic indicators such as MMP1, MMP2, MMP3 and MMP13 and inhibited aggrecan synthesis.
Lf is a robust regulator of chondrocyte metabolism, comparable to TGFbeta1. The catabolic influence together with the proliferative stimulus indicates a function as an early phase cytokine, enhancing MMPs, necessary for degradation of damaged tissue and stimulating proliferation of chondrocytes, necessary for reconstruction."

Again Lactoferrin stimulates chondrocyte proliferation and inhibits chondrocyte hypertrophy as indicated by the inhibition of aggrecans.  Lactoferrin is involved in signal transduction making it of particular interest to LSJL.

Lactoferrin promotes bone growth.

"In vitro, lactoferrin stimulates the proliferation of bone forming cells, osteoblasts, and cartilage cells at physiological concentrations (above 0.1 microg/ml). The magnitude of this effect exceeds that observed in response to other skeletal growth factors such as IGF-1 and TGFbeta. DNA synthesis is also stimulated in a bone organ culture system likely reflecting the proliferation of cells of the osteoblast lineage. Lactoferrin is also a potent osteoblast survival factor. In TUNEL and DNA fragmentation assays, lactoferrin decreased apoptosis, induced by serum withdrawal, by up to 70%. In addition, lactoferrin has powerful effects on bone resorbing cells, osteoclasts, decreasing osteoclast development at concentrations > 1 microg/ml in a murine bone marrow culture system. However, lactoferrin did not alter bone resorption in calvarial organ culture, suggesting that it does not influence mature osteoclast function. In vivo, local injection of lactoferrin in adult mice resulted in increased calvarial bone growth, with significant increases in bone area and dynamic histomorphometric indices of bone formation after only 5 injections. Taken together, these data demonstrate that the naturally-occurring glycoprotein lactoferrin is anabolic to bone in vivo, an effect which is consequent upon its potent proliferative and anti-apoptotic actions in osteoblasts, and its ability to inhibit osteoclastogenesis."

In this study it is suggested that Lactoferrin is more anabolic than TGF-Beta or IGF-1.

Lactoferrin is a potent regulator of bone cell activity and increases bone formation in vivo.

"Lactoferrin is an iron-binding glycoprotein present in epithelial secretions, such as milk, and in the secondary granules of neutrophils. We found it to be present in fractions of milk protein that stimulated osteoblast growth, so we assessed its effects on bone cell function. Lactoferrin produced large, dose-related increases in thymidine incorporation in primary or cell line cultures of human or rat osteoblast-like cells, at physiological concentrations (1-100 microg/ml). Maximal stimulation was 5-fold above control. Lactoferrin also increased osteoblast differentiation and reduced osteoblast apoptosis by up to 50-70%. Similarly, lactoferrin stimulated proliferation of primary chondrocytes. Purified, recombinant, human, or bovine lactoferrins had similar potencies. In mouse bone marrow cultures, osteoclastogenesis was dose-dependently decreased and was completely arrested by lactoferrin, 100 microg/ml, associated with decreased expression of receptor activator of nuclear factor-kappaB ligand. In contrast, lactoferrin had no effect on bone resorption by isolated mature osteoclasts. Lactoferrin was administered over calvariae of adult mice for 5 d. New bone formation, assessed using fluorochrome labels, was increased 4-fold by a 4-mg dose of lactoferrin. Thus, lactoferrin has powerful anabolic, differentiating, and antiapoptotic effects on osteoblasts and inhibits osteoclastogenesis."

So this study gives us some doses five fold above control.  Unlike other bone stimulating mechanisms, lactoferrin does not increase alkaline phosphatase activity and actually inhibits chondrocyte hypertrophy enabling chondrocyte proliferation to occur longer.  

"Comparable effects were found in primary cultures of human osteoblasts treated with bovine lactoferrin (Fig. 1D), and recombinant human lactoferrin was possibly more potent at low concentrations in these cells, increasing thymidine incorporation 2-fold at 10 µg/ml (data not shown). With this exception, the species of origin and method of preparation of the lactoferrin did not substantially impact the extent of the proliferative effect."


Effects of lactoferrin on the differentiation of pluripotent mesenchymal cells.

"We examined the effect of lactoferrin on the differentiation of pluripotent mesenchymal cells using a typical pluripotent mesenchymal cell line, C2C12. Cells were cultured in low-mitogen differentiation medium to induce cell differentiation, with or without the addition of lactoferrin. The cell lineage was determined by alkaline phosphatase (ALPase) activity, mRNA expression of cellular phenotype-specific markers using real-time polymerase chain reaction (PCR), and protein synthesis using Western blotting. The expression of low-density lipoprotein lipase receptor-related proteins (LRPs) 1 and 2, both lactoferrin receptors, was determined by reverse transcription-PCR. ALPase activity increased after the addition of lactoferrin. The mRNA expression of Runx2, osteocalcin, and Sox9 increased markedly as a result of lactoferrin treatment, whereas the expression of MyoD, desmin, and PPARgamma decreased significantly. Western blots showed that lactoferrin stimulation increased Runx2 and Sox9 proteins, whereas it decreased MyoD and PPARgamma synthesis. C2C12 cells expressed the LRP1 lactoferrin receptor. These results indicate that lactoferrin treatment converts the differentiation pathway of C2C12 cells into the osteoblastic and chondroblastic lineage."

More on Lactoferrin and Smad3:

Sustained co-cultivation with human placenta-derived MSCs enhances ALK5/Smad3 signaling in human breast epithelial cells, leading to EMT and differentiation.

"We investigated whether the interactions between mammary epithelial cells and human placenta-derived MSCs (hPMSC) affect the morphology, proliferation, and differentiation of epithelial cells in a co-culture system. We show that after co-culture with hPMSCs, human mammary epithelial cell lines (MCF-10F and HEMC) underwent significant morphologic alterations and a dramatic increase in ductal-alveolar branching, which was accompanied by a decrease or loss of the epithelial marker E-cadherin and a gain of the mesenchymal markers, alpha-SMA and vimentin. MCF-10F and HEMC proliferation was also inhibited in the presence of hPMSCs, and this retardation in growth was due to cell cycle arrest. Furthermore, in MCF-10F and HMEC cells, hPMSCs induced the production of lipid droplets, milk fat globule protein, and milk protein lactoferrin, which are markers of functional mammary differentiation. We also noticed an elevation in ALK5 and phosphorylated Smad3 protein levels upon hPMSC co-culture[so human placental cells increase lactoferrin levels]. Strikingly, the changes in morphology, proliferation, and differentiation were reversed by treatment with ALK5 or Smad3 knockdown in MCF-10F/hPMSC co-cultures. Collectively, our findings suggest that co-cultivation with hPMSCs leads to epithelial to mesenchymal transition (EMT) and differentiation of human breast epithelial cells through the ALK5/Smad3 signaling pathway."

"Lactoferrin [is] an iron-binding milk protein"

According to Differences in whey protein content between cow's milk collected in late pasture and early indoor feeding season from conventional and organic farms in Poland., lactoferrin levels were (Lf, 334.99 [Late Pasture] vs. 188.02 mg [early indoor feeding] L(-1) ).  So Lactoferrin levels in milk are not significantly higher in supplements than milk.

Lactoferring can be absorbed by humans and used by the body.

Bovine lactoferrin can be taken up by the human intestinal lactoferrin receptor and exert bioactivities.

"An intestinal enterocyte model (Caco-2 cells) was used to compare the ability of bovine LF (bLF) purified by our laboratory and CbLF[commercially available bovine-lactoferrin] with hLF[Human Lactoferrin] to resist digestion, bind to the receptor, and exert bioactivities, including cellular proliferation, differentiation, interleukin 18 secretion, and transforming growth factor-β1 expression.

bLf and CbLF, which are partially iron (Fe)-saturated, can bind additional Fe, partially resist digestion either dissolved in phosphate buffered saline or in the presence of infant formula at conditions similar to those of the infant gastrointestinal tract, and bind to Caco-2 cells in a manner similar to hLF. bLF and CbLF, as well as bound Fe, also are internalized by Caco-2 cells, as demonstrated by I and Fe labeling, albeit to somewhat less of an extent than hLF. CbLF promoted cell proliferation and differentiation to an extent similar to that of bLF and hLF, but these effects were not seen when the LF samples were saturated with Fe (holo-LF). Native forms of hLF and bLF significantly increased expression of transforming growth factor-β1, and holo-forms of LFs stimulated interleukin 18 secretion significantly, with the highest results for CbLF.

CbLF is biologically active and is likely to exert several of the bioactivities of hLF if added to infant formula."

"bLF and hLF and bLF purified from fresh cow's milk in the laboratory was predominantly in the apo-form, confirmed with a still high Fe-binding capacity, whereas hLF and purified bLF contained low amounts of LPS. LPS was practically absent in cbLF. Similar to hLF, purified bLF and cbLF were bound to human intestinal epithelial cells and were internalized because Fe was bound to them. At a pH similar to that of the human infant stomach, these bLFs partly resisted proteolytic degradation or were digested to immunoreactive fragments in vitro, whereas hLF was digested completely. Thus, it is possible that cbLF can be used as a supplement for application in products for infants and that it can achieve some of the functions of hLF."<-so milk lactoferrin from cows is best.

Lactoferrin: a biologically active molecule for bone regeneration.

"Lactoferrin, a member of the "Siderophilin" family, is an iron binding glycoprotein. Lactoferrin is produced by various exocrine glands in our body and is abundantly present in milk and colostrums. The uniqueness of lactoferrin as a skeletal regenerative molecule lies in its ability to favorably modulate the responses of the various cell types involved in musculoskeletal regeneration. Lactoferrin exhibits pleiotropic functions and recent studies indicate that lactoferrin promotes the proliferation and differentiation of osteoblast cells and inhibits osteoclast-mediated bone resorption. Human lactoferrin is also known to promote neovascularization. This review aims to summarize the most recent studies on lactoferrin focusing on its anabolic effect to bone tissue and the ability to modulate immune responses with specific focus on osteoimmunology."

On how Lactoferrin works:


Iron-saturated lactoferrin stimulates cell cycle progression through PI3K/Akt pathway.

"A relatively low level of ironsaturated Lf, Lf(Fe(3+)), can stimulate S phase cell cycle entry, and requires Akt activation in MCF-7 cells. Lf(Fe(3+)) immediately induced Akt phosphorylation at Ser473, which subsequently induced the phosphorylation of two G1-checkpoint Cdk inhibitors, p21(Cip/WAF1) and p27(kip1). The Lf(Fe(3+))-induced phosphorylation of Cdk inhibitors impaired their nuclear import behavior, thereby inducing cell cycle progression. However, the treatment of cells with a PI3K inhibitor, LY294002, almost completely blocked Lf(Fe(3+))-stimulated cell cycle progression. LY294002 treatment abrogated Lf(Fe(3+))-induced Akt activation, and prevented the cytoplasmic localization of p27(kip1). Higher levels of p21(Cip/WAF1) were also detected in the cytoplasmic sub-cellular compartment as a measure of cellular response to Lf(Fe(3+)). Consequently, the degree of phosphorylation of retinoblastoma protein was enhanced in response to Lf(Fe(3+)). Therefore, we conclude that Lf(Fe(3+)), as a potential antagonist of Cdk inhibitors, can facilitate the functions of E2F during progression to S phase via the Akt signaling pathway."

"Akt-induced p21 phosphorylation causes accumulation in the cytoplasm, thereby inactivating its inhibitory effects on Cdk2"

"ectopically expressed Lf might phosphorylate the p65 NF-κB subunit via signaling pathways including the TRAFs-NIK-IKK pathway"

Any form of Lactoferrin works not just bovine. It's hard to say exactly how much lactoferrin is optimal since this study was performed on rats but doses for humans seem to be around 250mg.  KAL - Colostrum Lactoferrin 1g/200mg - 60ct Cap .

Lactoferrin seems to be very promising both promoting chondrocyte proliferation and being anabolic to osteoblasts without seeming to inhibit endochondral ossification like some other bone stimulating mechanisms do.  However, the possibility of Lactoferrin to cause chondrocyte de-differentiation may give pause.  Since LSJL did not cause Smad3 signaling, Lactoferrin may help improve LSJL results.