Wednesday, December 22, 2010

Height Growth and Mesenchymal Chondrosarcoma

Mesenchymal chondrosarcoma is key proof that height increase is possible.  It involves UNCONTROLLED differentiation of stem cells into chondrocytes.  This lack of control is due to aberrant DNA Methylation which you can help prevent with Folic and Folinic Acid.  LSJL will not cause chondrosarcoma.  This study here shows that stem cells induced into chondrocytes from chondrosarcoma are capable of undergoing endochondral ossification.  Chondrosarcoma is capable of occurring within bone(inter osseous).  So with LSJL we are involving similar pathways as Chondrosarcoma with the exception that it is not uncontrolled and this lack of control is caused by genetic damage(prevent with anti-oxidants and Folic Acid, etc.).  Studying chondrosarcoma can provide a lot of insight into inducing hydrostatic pressure to cause mesenchymal stem cell differentiation into chondrocytes followed by hypertrophy and changing into an osteogenic phenotype.

Mesenchymal Chondrosarcoma of maxilla[A bone in the jaw]: A rare case report. 

"Mesenchymal chondrosarcoma (MC) is a rare variant of chondrosarcoma (CS). It is usually seen in younger age group compared to conventional CS and maxillary anterior alveolus is the most common site. It is a biphasic tumor with areas comprising of spindle cell mesenchyme interspread with areas of chondroid differentiation. A 75 year old male presented to us as a painless mass in maxilla. Contrast enhanced computed tomography (CECT) revealed a lytic expansile lesion in the left maxillary bone with foci of calcification within soft tissue lesion. Fine needle aspiration cytology (FNAC) and incisional biopsy was performed which confirmed the diagnosis of maxillary MC. The patient underwent right and left subtotal maxillectomy with 2 cm margins." 

In this study it grew into the mouth which is not something that can increase height really. 

Expression and function of matrix metalloproteinase (MMP)-28. 

"Matrix metalloproteinase-28 (MMP-28, epilysin) is expressed [in] a number of other normal human tissues. In epithelial cells, over-expression of MMP-28 mediates irreversible epithelial to mesenchymal transition concomitant with loss of E-cadherin from the cell surface and an increase in active transforming growth factor beta. MMP-28 [is expressed] in both cartilage and synovium. In human chondrosarcoma cells MMP-28 was activated by proprotein convertases and the active form of the enzyme preferentially associated with the extracellular matrix in a C-terminal independent manner. over-expression of MMP-28 in chondrosarcoma cells led to altered cell morphology with increased organisation of actin. Adhesion to type II collagen and fibronectin was increased, and migration across the former was decreased. MMP-28 was localised to the cell surface, at least transiently, in a C-terminal dependent manner. Heparin prevented both extracellular matrix association and cell surface binding of MMP-28 suggesting that both are via heparan sulphate proteoglycans. Over-expression of activatable MMP-28, but not catalytically inactive EA mutant increased the expression and activity of MMP-2, and all forms of MMP-28 tested increased expression of MMP19 and TIMP3 mRNA. Expression of MMP28 alters cell phenotype towards a more adhesive, less migratory behaviour.  MMP-28 activity may reside predominantly in the extracellular matrix." 

MMP-28 increases the organization of actin cytoskeleton.  Therefore, we want to inhibit MMP-28.  Increasing heparin levels may inhibit MMP-28.  MMP-28 is increased by TNF-alpha(LSJL inhibits TNF-alpha). 

Cytopathology of mesenchymal chondrosarcomas: a report and comparison of four patients.

"Four patients were diagnosed with MC at the authors' institution from 1994 to 2002. Three of four patients underwent fine-needle aspiration (FNA) biopsy as part of their diagnosis; in the fourth patient, imprint cytology was performed. Each tumor also received histologic confirmation.
The patients studied included three females and one male. In three patients, the tumor presented initially as a soft tissue mass; whereas, in the remaining patient, the MC presented in the tibia. FNA results demonstrated small, oval-to-spindled cells with high nuclear-to-cytoplasmic ratios. Cells occurred singly and in clumps in a background of basophilic extracellular matrix. Histologic examination of each lesion demonstrated biphasic tumors, including focal areas of relatively mature cartilage formation as well as a small cell population.
MC is a rare soft tissue tumor that occurs frequently in extraskeletal locations. FNA of these tumors can be diagnostic if the tumor is sampled appropriately and of critical features, such as the background extracellular matrix, are recognized. Given the propensity of these tumors to metastasize and the poor prognosis of patients with MC, early identification by FNA biopsy may allow earlier, more aggressive interventions." 

The individual with the mesenchymal chondrosarcoma in the femur was 15 and there was no mention about whether height increased. 

I couldn't find any instances of chondrosarcomas in long bones in adults but if it can occur outside the skeleton then why couldn't it occur in long bones  Could have to do with telomere length: 

[Correlation of telomere length and the expression of its regulating proteins in mesenchymal sarcomas].

"The telomere length in 20 cases of osteosarcomas, 25 of chondrosarcomas, 19 of rhabdomyosarcomas, 26 of liposarcomas was measured by telomere fluorescence in situ hybridization (Telo-FISH), and the expression of TRF1, POT1, hTERT, p53 or c-myc was analyzed by immunohistochemistry, respectively.
The telomere length in osteosarcomas was significantly shorter than that of either chondrosarcomas or liposarcomas[telomere length correlates to chondrogenic potential?]. Similarly, the telomere length of rhabdomyosarcoma was shorter than that of chondrosarcoma. Meanwhile, telomere shortening was positively correlated with down expression of telomere binding proteins TRF1 and POT1[increasing expression of telomere binding proteins may be a good thing to investigate], but trends were detected more frequently in positive expression of hTERT and in nuclear accumulation of P53 or expression of c-myc. With advancing in histological grading, telomere length was shortened markedly in chondrosarcomas[as chondrocytes progress to osteoblasts their telomeres shorten], especially in liposarcomas.
 The shortening of telomere could prevail in mesenchymal sarcoma and reflect the malignant potential. Telomere attrition usually correlated with down expression of POT1, TRF1 and with increased levels of hTERT, P53 and c-myc."

One method to reduce telomere shortening so far has been supplementation with Astragalus Membranaceus.  Shortened telomeres could be why there is such a low instance of long bone mesenchymal chondrosarcomas during aging.  In turn we can conclude that if we want to maintain the effectiveness of LSJL during aging we should try to keep our telomeres long to enable induction of stem cells to a chondrogenic phenotype.

Low-grade fibromyxoid sarcoma with prominent giant rosettes and heterotopic ossification.

"Low-grade fibromyxoid sarcoma is a rare soft tissue sarcoma of fibroblastic differentiation characterized by a deceptively benign morphologic appearance with almost consistent MUC4 expression and recurrent chromosomal translocations, t(7;16)(q34;p11) and t(11;16)(p11;p11), resulting in the FUS-CREB3L2 and FUS-CREB3L1{CREB3L1 is upregulated in LSJL} fusion genes, respectively. A subset of the tumors show peculiar histologic features, designated as giant rosettes, and were formerly referred to as hyalinizing spindle cell tumor with giant rosettes. We herein report a case of low-grade fibromyxoid sarcoma showing the presence of numerous giant rosettes, with and without collagenous centers, distributed throughout the lesion and unusual rim-like heterotopic ossification. Such a case might present a diagnostic challenge. The diagnosis of the tumor was confirmed by positive immunoreactivity to MUC4 and the FUS-CREB3L2 fusion detected by molecular testing using formalin-fixed, paraffin-embedded tissue."

No chondrogenic genes were affected so CREB3L1 is not sufficient for chondrogenesis.

BMP and TGFbeta pathways in human central chondrosarcoma: enhanced endoglin and Smad 1 signaling in high grade tumors.

"Gene expression analysis was performed by quantitative RT-PCR in 26 central chondrosarcoma and 6 healthy articular cartilage samples. Expression of endoglin and nuclear localization of phosphorylated Smad1/5/8 and Smad2 was assessed by immunohistochemical analysis.
The expression of TGFB3 and of the activin receptor-like kinase ALK2 was found to be significantly higher in grade III compared to grade I chondrosarcoma. Nuclear phosphorylated Smad1/5/8 and Smad2 were found in all tumors analyzed and the activity of both signaling pathways was confirmed by functional reporter assays in 2 chondrosarcoma cell lines. Immunohistochemical analysis furthermore revealed that phosphorylated Smad1/5/8 and endoglin expression were significantly higher in high-grade compared to low-grade chondrosarcoma and correlated to each other.
The BMP and TGFbeta signaling pathways were found to be active in central chondrosarcoma cells. The correlation of Smad1/5/8 activity to endoglin expression suggests that, as described in other cell types, endoglin could enhance Smad1/5/8 signaling in high-grade chondrosarcoma cells. Endoglin expression coupled to Smad1/5/8 activation could thus represent a functionally important signaling axis for the progression of chondrosarcoma and a regulator of the undifferentiated phenotype of high-grade tumor cells."

"Conventional central chondrosarcomas are cartilaginous tumors which arise centrally within the medullar cavity of bone. They represent 75% of all malignant cartilage tumors. Lowgrade chondrosarcoma displays a hyaline cartilage matrix with low cell density, and an abundance of hyaline cartilage matrix, no mitoses and cells with a chondrocyte-like morphology. While these tumors generally do not metastasize, they can progress to highgrade chondrosarcomas which are characterized by a muco-myxoid matrix, a high density of cells with increased mitotic rates and elevated vascularization. At the periphery of the lobules of high-grade chondrosarcoma, cells may become spindle-shaped"

"In endothelial cells and chondrocytes, the TGFβ/ALK1/Smad1 signaling axis appears to be favored in presence of the TGFβ co-receptor endoglin, also known as CD105"

"PAI1 [is] a target gene of TGFβ/Smad2/3 [and] showed higher levels in high grade tumors"<-LSJL downregulates PAI1 as Serbp1.

BMP2 has a migulatory effect on chondrosarcoma cell lines.

"Compared to normal cartilage, chondrosarcoma showed altered expression levels for BMP2 and BMP7. BMP2 was significantly higher expressed in normal cartilage samples than in chondrosarcoma (37.8-fold, p<0.001), while BMP7 was not detected or found at very low expression levels in normal cartilage samples and was significantly higher expressed in chondrosarcoma (29.4-fold, p=0.005)."

"in chondrosarcoma no hypertrophic differentiation occurs and we have observed that phosphorylated Smad1/5/8 was elevated in high-grade tumors with a less differentiated phenotype. Other mechanisms such as elevated PTHrP signaling in chondrosarcoma may be blocking hypertrophy in these tumors"

"Endoglin expression is up-regulated during the dedifferentiation of chondrocytes and conversely down-regulated during the chondrogenic differentiation of mesenchymal stem cells. In marrow stromal cell lines, endoglin was shown to stimulate proliferation"

Chondrosarcoma: with updates on molecular genetics.

"Chondrosarcoma (CHS) is a malignant cartilage-forming tumor and usually occurs within the medullary canal of long bones and pelvic bones."

"Radiographs of conventional CHS typically reveal a mixed lytic and sclerotic pattern with characteristic small calcifications, often referred as “popcorn” or “ringlets” calcifications. In the long bones, primary CHS most commonly involves the metaphysis (49%), followed by the diaphysis (36%)"<-metaphysis is the epiphyseal bone marrow which we are trying to target with LSJL.

A slice from the bone of a metaphysis chondrosarcoma.(distal femur)
Chondrosarcoma of the diaphysis and metaphysis.(proximal femur)

"Of the Indian hedgehog (IHH)/parathyroid hormone-related protein (PTHLH) pathway, induction of the PTHLH pathway and reactivation of bcl2 have been implicated in pathogenesis and progression of conventional CHS, and bcl2 was suggested to be a reliable marker for the distinction between low-grade CHS and enchondromas"

"Immunohistochemically, the cartilaginous area is strongly positive for S-100 protein, whereas only scattered single cells in the undifferentiated areas stain for this antigen. The undifferentiated small cell component of mesenchymal CHSs is consistently positive for CD99 and may stain for vimentin {up} and Leu7 while negative for osteocalcin, actin, cytokeratin, and epithelial membrane antigen (EMA)"

"[clear cell chondrosarcoma] is typically located in the epiphysis metaphysis of long bone."<-Clear cell refers to the clear cytoplasm of tumor cells.

"The lesion is lytic, slightly expansile, and well delineated from the adjacent normal bone."

"Mesenchymal chondrosarcomas are small-cell malignancies named as chondrosarcomas due to the focal appearance of cartilage islands. In this study, the use of in situ detection techniques on a large series of mesenchymal chondrosarcoma specimens allowed the identification of tumor-cell differentiation pathways in these neoplasms. We were able to trace all steps of chondrogenesis within mesenchymal chondrosarcoma by using characteristic marker genes of chondrocytic development. Starting from undifferentiated cells, which were negative for vimentin and any other mesenchymal marker, a substantial portion of the cellular (undifferentiated) tumor areas showed a chondroprogenitor phenotype with an onset of expression of vimentin and collagen type IIA. Cells in the chondroid areas showed the full expression panel of mature chondrocytes including type X collagen indicating focal hypertrophic differentiation of the neoplastic chondrocytes. Finally, evidence was found for transdifferentiation of the neoplastic chondrocytes to osteoblast-like cells in areas of neoplastic bone formation[endochondral ossification is typified by apoptosis of chondrocytes rather than transdifferentiation]. These results establish mesenchymal chondrosarcoma as the very neoplasm of differentiating premesenchymal chondroprogenitor cells. The potential of neoplastic bone formation in mesenchymal chondrosarcoma introduces a new concept of neoplastic (chondrocytic) osteogenesis in musculoskeletal malignant neoplasms, which qualifies the old dogma that neoplastic bone/osteoid formation automatically implies the diagnosis of osteosarcoma."

"The expression of COL2B together with aggrecan proteoglycan is the hallmark of differentiated chondrocytes in the areas of microscopically visible cartilaginous matrix formation. In these areas, cells are positive for S-100 protein, which is one marker for physiological and neoplastic chondrocytic differentiation."

"The formed cartilage shows histochemically and immunohistochemically all features of fetal hyaline cartilage, thus, confirming previous morphological and ultrastructural studies."

1 comment:

  1. Thanks for always providing so much information!

    Have you by the way read anything about the increase in height of pregnant women?

    Could you please explain this using your model of bone lengthening? Such incidences demonstrate that it certainly is possible for some individuals to grow even after puberty.