Sunday, June 20, 2010

Increasing Bone Growth with PI3K?

PI-3 Kinase is a subset of enzymes that are involved in cellular proliferation and differentiation.  Stem cells and chondrocytes are cells.  Increasing profileration of these cells could be responsible for increasing bone growth.

How does PI3K work to increase height?  How can we manipulate levels of this protein kinase? 

Insulin stimulates osteoblast proliferation and differentiation through ERK and PI3K in MG-63 cells. 

"To explore the mechanisms of action of insulin on osteoblast growth and differentiation, human osteoblastic cell line-MG-63 was used and stimulated by insulin in the presence or absence of ERK inhibitor PD98059, PI3-K inhibitor LY294002, or inhibitor PD98059 + LY294002. The results showed that insulin positively regulated the expression of its receptor. Insulin stimulated the proliferation of MG-63 cells in a time- and dose-dependent manner and blockade of both MAPK and PI3K pathways could inhibit the cell proliferation. In addition, ALP activity, the secretion of type I collagen, OC gene expression, and mineralized nodule formation were increased in the insulin treated group, whereas these indicators were decreased after treatment with blocking agents. However, treatment with PI3-K inhibitor LY294002 significantly reversed the down-regulation of Runx2 expression and treatment with ERK inhibitor PD98059 remarkably decreased up-regulation of Osx and IGF-1 expression after insulin treatment.  Insulin promoted osteoblast proliferation and differentiation through MAPK and PI3K pathway in MG-63 cells." 

This confirms that increasing insulin sensitivity can increase height at least in the torso where increasing osteoblast proliferation is what causes height increase there.  PI3K enzymes are needed to increase height but it is ultimately the level of insulin that regulates how much height is gained. 

Is PI3K involved in chondrocytes? 

Regulation of gene expression by PI3K in mouse growth plate chondrocytes. 

"Pharmacological inhibition of the PI3K signaling pathway results in reduced endochondral bone growth, and in particular, shortening of the hypertrophic zone in a tibia organ culture system. In this current study we aimed to investigate targets of the PI3K signaling pathway in hypertrophic chondrocytes. Through the intersection of two different microarray analyses methods (classical single gene analysis and GSEA) and two different chondrocyte differentiation systems (primary chondrocytes treated with a pharmacological inhibitor of PI3K and microdissected growth plates), we were able to identify a high number of genes grouped in GSEA functional categories regulated by the PI3K signaling pathway. Genes such as Phlda2 and F13a1 were down-regulated upon PI3K inhibition and showed increased expression in the hypertrophic zone compared to the proliferative/resting zone of the growth plate. In contrast, other genes including Nr4a1[up in LSJL] and Adamts5 were up-regulated upon PI3K inhibition and showed reduced expression in the hypertrophic zone. Regulation of these genes by PI3K signaling was confirmed by quantitative RT-PCR. We focused on F13a1 as an interesting target because of its known role in chondrocyte hypertrophy and osteoarthritis. Mouse E15.5 tibiae cultured with LY294002 (PI3K inhibitor) for 6 days showed decreased expression of factor XIIIa in the hypertrophic zone compared to control cultures. Discovering targets of signaling pathways in hypertrophic chondrocytes could lead to targeted therapy in osteoarthritis and a better understanding of the cartilage environment for tissue engineering." 

"inhibition of PI3K signaling results in reduced growth of tibiae"

#2 are genes upregulated by PI3K inhibition.  So genes downregulated by PI3K in growth plate chondrocytes.  #1 genes are genes upregulated in control but not #2 so genes upregulated by PI3K.

Akt is a downstream target of PI3K and LSJL increases p-Akt.

The role of Akt1 in terminal stages of endochondral bone formation: angiogenesis and ossification.

"The PI3K signaling pathway [has a role] in chondrocyte hypertrophy and bone growth. We aimed to investigate the role of Akt1, an important target of PI3K, in endochondral ossification. Akt1 KO mice showed reduced size compared to their littermates throughout life, but the largest difference in body size was observed around 1 week of age. Focusing on this specific developmental stage, we discovered delayed secondary ossification in the long bones of Akt1 KO mice. A delay in formation of a structure resembling a secondary ossification center was also seen in tibia organ cultures treated with the PI3K inhibitor LY294002. The expression of matrix metalloproteinase-14 (MMP-14) [Upregulated by LSJL], the main protease responsible for development of secondary ossification centers, was decreased in the epiphysis of Akt1 KO mice, possibly explaining the delay in secondary ossification centers seen in the Akt1 KO mice. Bone mineral density (BMD) and bone mineral content (BMC) measured in the proximal tibia of 1-year-old mice were decreased in Akt1 KO mice, suggesting that the original delay in ossification might affect bone quality in older animals."

"Akt1-deficient mice showed reduced body weight, dwarfism, and decreased bone mass (at 8 weeks of age). Akt2 mutants have a diabetes-like syndrome and mild growth deficiency"

"In Akt1 KO littermates we noticed vascular cartilage canals (VC) in the tibia and peripheral vascular invasion in the femur"

"[The] defect in ossification was due to a delay in secondary ossification formation in the Akt1 mutants compared to control littermates"

"reduced MMP-14 expression in our mutant mice contributes to the delay in secondary ossification"

So the PI3K enzyme is important for getting chondrocytes to hypertrophy.  Larger hypertrophy of chondrocytes should increase bone growth and that is what pushes the bones apart in the hyaline cartilage growth plate line.  

The proper function of the PI3K enzyme pathway is important for proper growth but ultimately it is other factors that ultimately manipulate growth like insulin.  There are PI3K inhibitors(for anti-cancer) but there are no PI3K stimulators on the market. 

To grow taller at times it seems as simple as looking at what they are trying to cure cancer and then do the opposite.  Not in this case however as the PI3K pathway that affects proliferation and differentiation seems to be either off or on.

1 comment:

  1. I think i read somewhere that chromium pycolinate increases insulin sensitivity.

    Also, a weightlifting supplement that heavily emphasizes insulin is Cell Tech.