Tuesday, February 23, 2010

Factors that affect chondrocyte proliferation

The same process of endochondral ossification is used to both naturally increase height and to heal fractures.  It is also used to heal microfractures dependent on the type of microfracture it is.  Chondrocytes are an important part of endochondral ossification and can result in height increase as chondrocytes can reproduce dependent on telomere length and DNA Methylation status. Chemical signaling mechanisms like Growth Hormone have failed to reproduce Gigantism likely due to these two factors.  However, there still has to be a reason that Gigantism exists. Still, chemical and dietary means of increasing chondrocyte proliferation can result in faster healing of fractures plus faster endochondral ossification and therefore faster increasing of height.

Effect of Nell-1 Delivery on Chondrocyte Proliferation and Cartilaginous Extracellular Matrix Deposition

"Cartilage tissue engineering using chondrogenic growth factors is an attractive strategy to promote cartilage repair. Bone morphogenetic proteins have been widely studied for their application in cartilage repair. However, functional heterogeneity of bone morphogenetic proteins and unpredictable effects such as cyst formation may limit their therapeutic use. Thus, the use of alternative growth factors with greater osteochondral specificity may be advantageous for cartilage regeneration. Nel-like molecule-1 (Nell-1; Nel is a protein strongly expressed in neural tissue encoding epidermal growth factor-like domain) is a novel growth factor believed to specifically target cells committed to the osteochondral lineage. Mutation of the Nell-1 gene has been shown to disrupt normal cartilage growth and development in rodents. This study investigates the chondrogenic potential of recombinant human Nell-1 protein in a three-dimensional alginate hydrogel microenvironment containing rabbit chondrocytes. To provide controlled delivery and maximize biological efficiency, Nell-1 was incorporated in chitosan microparticles. Over 42 days of culture, chondrocyte proliferation and cluster formation was significantly enhanced by Nell-1 in a dose-dependent manner. Further, the clusters formed in the presence of Nell-1 contained more type II collagen and glycosaminoglycans than clusters formed within Nell-free control gels. These findings demonstrate the ability of Nell-1 to promote chondrocyte proliferation and deposition of cartilage-specific extracellular matrix materials."

Currently, there are no food or supplements that contain Nell-1 but it is patented so one can assume that future products will appear on the horizon(given how many things are turned into supplements).   Nell-1 definitely increases growth rate but whether Nell-1 will actually increase height is unknown.

Mechanisms of impaired growth: effect of steroids on bone and cartilage.

"Systemically, GC(glutocorticoids-an example is cortisol) treatment reduces circulating levels of estrogen and modestly increases parathyroid hormone levels. At the local level, GCs decrease insulin-like growth factor I (IGF-I) production, induce IGF-I resistance and increase nuclear factor kappaB ligand(also known as RANKL) production by osteoblasts. These alterations inhibit new bone formation and stimulate bone resorption, with a net loss of bone over time. Clinically, this results in decreased bone mineral density, osteoporosis and increased risk for fracture. Local effects of GCs at the growth plate include reduction of IGF-I production, inducing IGF-I resistance and reducing production of C-type natriuretic peptide[the C-type natruiretic peptide is very important in height growth, overexpression of CNP has resulted in enhanced height growth], which results in a reduction of chondrocyte proliferation, matrix synthesis and hypertrophy. These reductions in chondrocyte function result in decreased linear growth."

Glutocorticoids are a specific type of steroid.  We know that bodybuilders are always trying to find ways to lower their cortisol.  It's unclear whether there's catch up production of CNP in response to say increased cortisol levels.

SCF, BDNF, and Gas6 are regulators of growth plate chondrocyte proliferation and differentiation.

"Bovine epiphyseal chondrocytes separated by density gradient centrifugation differ in proliferative response to IGF-I and IGF-I receptor number. To identify novel modifiers of IGF-I action at the growth plate, we used microarray analyses to compare bovine hypertrophic and reserve zones and identified several receptors differentially expressed across the growth plate: NTRK2 [receptor for brain-derived neurotrophic factor (BDNF)], KIT [receptor for stem cell factor (SCF)], and MER and AXL [two receptors for growth arrest-specific 6 (Gas6)]. The corresponding ligands were tested for their ability to stimulate either proliferation of isolated chondrocytes or differentiation in ATDC5 cells. Each factor inhibited IGF-I-mediated proliferation in isolated chondrocytes by attenuating ERK1/2 activation[so NTRK2, KIT, MER, and AXL dampen ERK1/2 activation]. SCF, BDNF, Gas6, and C-type natriuretic peptide promoted differentiation in ATDC5 cells[Since CNP can increase height maybe SCF, BDNF, and Gas6 can increase height as well], each factor producing different expression patterns for collagen X, collagen 2, aggrecan, and lysyl oxidase. Whereas multiple factors stimulated ATDC5 differentiation, only IGF-I and high-dose insulin, out of several factors implicated in chondrocyte maturation, stimulated proliferation of isolated chondrocytes. IGF-I appears to be the primary proliferative signal in growth plate chondrocytes, whereas multiple factors including SCF, BDNF, and Gas6 regulate the pace of differentiation at the growth plate."

IGF-1 is what primarily increases chondrocyte proliferation but SCF, BDNF, Gas6, and CNP may increase height at other stages of growth. 

Both Chondroinduction and Proliferation Account for Growth of Cartilage Nodules in Mouse Limb Bud Cultures.

"High density micromass culture of limb bud mesenchymal stem cells isolated from mouse embryos represents a well-established model to study chondro- and osteogenesis. To determine whether cartilage nodules grow solely by induction of surrounding cells or proliferation of cells within the nodules, we performed BrdU/Collagen II (Col II) double-labelling and 3D reconstruction of growing cartilage nodules. Col II-positive replicating chondrocytes are present throughout the nodules with the majority of replicating cells localized on the top (cell-medium interface) and periphery/sides of nodules. Kinetic analysis of cellular proliferation within the nodules demonstrated the time-dependent reduction in number of Col II-positive replicating cells. The sequential expression of Col I, Col II, Col X, parathyroid hormone related peptide receptor 1 (Pthr1), bone sialoprotein (Bsp) and osteocalcin (Ocn) mRNAs was similar to that characterizing chondrocyte differentiation and maturation in vivo. We conclude that the limb bud model recapitulates events seen during endochondral bone formation: cellular aggregation, proliferation, differentiation and maturation to hypertrophy. We also conclude that not only induction of peri-nodular mesenchymal cells but also proliferation of chondrocytes within cartilage nodules contribute to cartilage nodule growth."

Decrease in chondrocyte proliferation(inferred from decrease in Type II Collagen) occurred before decrease in chondrocyte hypertrophy meaning that perhaps maintaining chondrocyte proliferation can ward off growth cessation.

This study to be analyzed in more detail in the future.

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