Tuesday, June 12, 2012

Grow Taller with Kartogenin

Kartogenin is unfortunately not yet available for sale but it neems very promising.

A stem cell-based approach to cartilage repair.

"Kartogenin promotes chondrocyte differentiation (median effective concentration = 100 nM), [and] shows chondroprotective effects in vitro. Kartogenin binds filamin A, disrupts its interaction with the transcription factor core-binding factor β subunit (CBFβ), and induces chondrogenesis by regulating the CBFβ-RUNX1 transcriptional program."

So anything else that disrupts the interaction between filamin A and CBF-Beta could help you grow taller.

"Chondrogenic nodules containing cartilage-specific matrix components (proteoglycans and type II collagen) were positively stained by rhodamine B to identify the early cell condensation phenotype associated with the induction of chondrogenesis"<-So in the LSJL rats rhodamine B should be used to determine if LSJL can induce chondrogenesis.  Rhodamine B is $109(http://www.coleparmer.com/buy/product/40083-rhodamine-b-laser-grade-99-1g-yo-88356-02.html) if any scientists want to do experiments with LSJL and seeing if it can induce chondrogenesis in bone marrow MSCs.  The scientist would need to lend the pizeoactuator loading device from Ping Zhang.

"Lineage-specific differentiation in the presence of KGN was further confirmed by fluorescent immunostaining of chondrocyte-specific proteins, including type II collagen, SOX9, and aggrecan under both monolayer and high-density conditions"

"CBFβ is the regulatory subunit of the heterodimeric core-binding factor transcription complex; the other subunit is one of the runt-related transcription factor (RUNX) family members, which include RUNX1, RUNX2, and RUNX3. In the resting state, CBFβ is sequestered in the cytoplasm by binding to its cytoplasmic partner, FLNA; upon activation, it dissociates from FLNA and translocates into the nucleus, where it binds the RUNX factors and regulates transcription. When hMSCs were treated with 5 μM KGN, CBFβ nuclear localization was significantly increased. We next overexpressed CBFβ in hMSCs and saw that cells overexpressing CBFβ showed increased chondrocyte differentiation as compared to empty vector–transfected cells. Moreover, knockdown of CBFβ expression by shRNAs blocked KGN’s effect on chondrocyte differentiation in hMSCs. Thus, KGN appears to induce chondrogenesis by regulating the nuclear localization of CBFβ."<-So upregulating CBFBeta can help you grow taller.

"RUNX1 [plays] a critical role in chondrogenesis, chondrocyte proliferation, and survival"

Replenishing Cartilage from Endogenous Stem Cells

"Kartogenin binds to the carboxyl end of filamin A, displacing CBFβ from its cytoplasmic binding site. CBFβ is thus freed to enter the nucleus, where it binds to the DNA-binding transcription factor RUNX1. The CBFβ–RUNX1 complex activates the transcription of proteins involved in cartilage differentiation, increases the synthesis of components of the cartilage matrix (such as collagen type II, aggrecan, and tissue inhibitors of metalloproteinases), and protects cartilage against stress factors."

"kartogenin partially suppressed the release of both proinflammatory nitric oxide and the glycosaminoglycan by-products of tissue destruction in articular chondrocyte cultures and cartilage explants."

Kartogenin: a game-changer in regenerative medicine

"Chemical agents stimulate endogenous somatic stem cells to regenerate. Using primary bone marrow MSCs in an image-based high-throughput screening assaying for chondrogenic nodule formation, kartogenin was identified out of a library of 22,000 structurally diverse molecules. This molecule was validated for in vitro chrondrocyte differentiation in a dose-dependent manner (EC50 = 100 nM). Intra-articular administration of kartogenin promoted cartilage repair in two rodent models. Although an in vitro EC50 of 100 nM was reported, in vivo experiments required up to 100 µM doses to promote cartilage repair. 48-h treatment of 100 µM kartogenin does not induce caspase 3 activation in human MSCs, chrondrocytes, osteoblasts or synoviocytes. Kartogenin’s mechanism of action involves targeting filamin A to disrupt the interaction with CBFβ in order to induce chrondrogenesis via a CBFβ–RUNX1 transcription program."

This compound looks really promising. Too bad you can't yet buy it. And you wouldn't want Kartogenin in anywhere else but the bone marrow. We could also look for other targets that increase Runx1

More on CBFB and Runx1:

Requisite roles of Runx2 and Cbfb in skeletal development.

"Runx2 determines the lineage of osteoblastic cells from multipotent mesenchymal cells, enhances osteoblast differentiation at an early stage, and inhibits osteoblast differentiation at a late stage. Runx2 is involved in the production of bone matrix proteins. Runx2 is a positive regulator of chondrocyte maturation and is involved in vascular invasion into the cartilage. Core binding factor beta (Cbfb) is a cotranscription factor which forms a heterodimer with Runx proteins. Cbfb is required for the functions of Runx1 and Runx2. Runx2/Cbfb heterodimers play essential roles in skeletal development."

"The Runx family proteins, which consist of Runx1, Runx2, and Runx3, have a DNA binding domain, runt, that is homologous to the Drosophila pair rule gene, runt. Core binding factor (Cbfb) is a cotranscription factor that does not contact DNA directly and enhances the in-vitro DNA binding of the
runt protein"

"Runx1 is essential for hematopoietic stem cell differentiation"

"Runx2 [KO] mesenchymal cells completely lack the ability to differentiate into osteoblasts, but retain the capacity to differentiate into adipocytes and chondrocytes"

"In prechondrogenic ATDC5 cells, DN-Runx2, which inhibits all Runx proteins, inhibits cellular condensation, suggesting that Runx proteins may be involved in an early step of chondrogenesis."

"Runx2 is involved in determining whether chondrocytes acquire a permanent or transient phenotype"

"In Cbfb- /- tg mice, intramembranous bones were poorly formed by immature osteoblasts, chondrocyte maturation was severely inhibited, and no endochondral bones were formed."

"Cbfb [is] required in the DNA binding of Runx2 and in Runx2-dependent transcriptional activation."

New targets for disease modifying osteoarthritis drugs: chondrogenesis and Runx1

(TD-198946) has strong chondrogenic activity but does not promote chondrocyte hypertrophy.  "TD-198946 exerts its effect through regulating the expression of Runx1"

Figure 1
How MSCs might differentiate into chondrocytes in the joint capsule.  This perhaps could be translated to within the epiphysis since that's whether the MSCs come from in the first place.  Also this drug could be used for intraepiphyseal chondroinduction.

"MSC can reach the sinovium by migration from systemic circulation or from haematopoietic marrow through subchondral bone. "

"Intra-articular administration of drugs increasing the Rux1 expression can induce chondrogenesis and block hypertrophy "

"KGN has the capacity to induce chondrogenesis by regulating the binding of the core-binding factor β subunit (CBFβ) to Filamina A (FLNA) or Runx1. FLNA is an actin-binding protein that cross-links actin filaments and its expression is increased in OA human mesenchymal stem cells (MSCs). The binding of CBFβ to Runx1 induces chondrogenesis; however, its binding to FLNA reduces chondrogenesis. KGN blocks the interaction between FLNA and CBFβ, promoting translocation into the nucleus of CBFβ where it binds to Runx1 and regulates transcription and chondrogenesis. Lineage-specific differentiation in the presence of KGN was confirmed by fluorescent immunostaining of chondrocyte-specific proteins, including type II collagen, Sox9 and aggrecan"

Kartogenin promotes mouse embryo limb joint formation and skeletal growth but I couldn't get it from the osteoarthritis and cartilage website.

Genes & cells: Inducing cells to make cartilage: Kartogenin triggers activity that could fight osteoarthritis

"Kartogenin steers the stem cells to wake up and take on cartilage-making duties"

" kartogenin, induced stem cells to take on the characteristics of chondrocytes. The molecule turned on genes that make cartilage components called aggrecan and type II collagen."

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