Grow Taller with Hyaline Cartilage?

Since Hyaline Cartilage is the type of cartilage within the resting zone of the growth plate, it is a very important type of cartilage to know about.  The resting zone of the growth plate is where the stem cells are located which we want to increase proliferation of with Lithium or IGF-1.  Although mesenchymal stem cells do have the ability to generate new cartilage from nowhere(and thereby a new growth plate) it would be useful to know whether the growth plate line consists of hyaline cartilage.  It doesn't make sense for the layer of hyaline cartilage to ever go away because the other layers undergo apoptosis and are eventually replaced by bone.  Hyaline cartilage does seem to ossify but it occurs after the rest of the apoptosis.  Hyaline cartilage seems to be the extracellular matrix product of chondrocytes.  You can increase the serum level of the bone marrow of various extracellular matrix components like by supplementation of Hyaluronic Acid.

Reappraisal of mesenchymal chondrosarcoma: novel morphologic observations of the hyaline cartilage and endochondral ossification and beta-catenin, Sox9, and osteocalcin immunostaining of 22 cases. 

"Mesenchymal chondrosarcoma, a rare malignant round cell and hyaline cartilage tumor, is most commonly intraosseous but can occur in extraskeletal sites. We intensively observed the morphology and applied Sox9 (master regulator of chondrogenesis), beta-catenin (involved in bone formation, thought to inhibit chondrogenesis in a Sox9-dependent manner), and osteocalcin (a marker for osteoblastic phenotype) to 22 central nervous system and musculoskeletal mesenchymal chondrosarcoma. Immunohistochemistry and follow-up were obtained on mesenchymal chondrosarcoma and tumor controls. Twenty-two mesenchymal chondrosarcomas included 5 central nervous system (all female; mean age, 30.2; mean size, 7.8 cm; in frontal lobe [n = 4] and spinal cord [n = 1]) and 17 musculoskeletal (female-male ratio, 11:6; mean age, 31.1; mean size, 6.2 cm; 3 each of humerus and vertebrae; 2 each of pelvis, rib, tibia, neck soft tissue; one each of femur, unspecified bone, and elbow soft tissue). The hyaline cartilage in most tumors revealed a consistent linear progression of chondrocyte morphology, from resting to proliferating to hypertrophic chondrocytes[What does this sound like?  Yup.  The growth plate.]. Sixty-seven percent of cases demonstrated cell death and acquired osteoblastic phenotype, cells positive for osteocalcin at the site of endochondral ossification. Small round cells of mesenchymal chondrosarcoma were negative for osteocalcin. SOX9 was positive in both components of 21 of 22 cases of mesenchymal chondrosarcoma. beta-Catenin highlighted rare nuclei at the interface between round cells and hyaline cartilage in 35% cases. Control skull and central nervous system cases were compared, including chondrosarcomas and small cell osteosarcoma, the latter positive for osteocalcin in small cells. Mesenchymal chondrosarcoma demonstrates centrally located hyaline cartilage with a linear progression of chondrocytes from resting to proliferative to hypertrophic, which undergoes endochondral ossification, recapitulating growth plate cartilage and suggesting that this component of mesenchymal chondrosarcoma may be a differentiated (benign or metaplastic) component of a malignant metastasizing tumor. This hyaline cartilage component is morphologically different from cartilage of control chondrosarcoma. Mesenchymal chondrosarcoma can be separated from small cell osteosarcoma, using Sox 9 for cartilage and osteocalcin for osteoblastic phenotype. Rare nuclear beta-catenin expression at the interface between hyaline cartilage and small round cells potentially implicates the APC/Wnt pathway during endochondral ossification in morphologically benign hyaline cartilage component of mesenchymal chondrosarcoma." 

This mesenchymal stem cancer cell was able to replicate the growth plate in almost any hyaline cartilage layer(given the presence of Sox9 and beta-catenin).  67% of the hyaline cartilage layers were able to finish the job and turn into bone.  Sox9 helps provide nutrients to the chondrocytes and unless Sox9 becomes absent the chondrocytes won't die and turn into bone. 

"Histologically, mesenchymal chondrosarcoma has a characteristic biphasic pattern composed of a cellular poorly differentiated small round blue cell component interspersed with islands of well-differentiated hyaline cartilage."

"The hyaline cartilage in most mesenchymal chondrosarcomas showed apparent linear progression of chondrocytes from primitive “resting” chondrocytes to proliferating chondrocytes and then hypertrophic chondrocytes, which underwent visible cell death and endochondral bone formation, recapitulating normal growth plate cartilage"

Histology of chandrosarcoma. "Mesenchymal chondrosarcoma is biphasic with small round cell and centrally located hyaline cartilage components (A-C) and bone formation (A-D; see arrow, A). Bone formation is central but located in the top portion of B. The hyaline cartilage in mesenchymal chondrosarcoma is morphologically benign as it often appears to progress in a zonal pattern from small resting, chondrocytes to proliferating, then hypertrophic chondrocytes that die and become replaced by bone, via endochondral ossification. The interface between the cartilage and bone has chondrocyte swelling then linear chondrocyte cell death (D, arrows) and replacement of cartilage template by bone, recapitulating long bone growth plate."

"Sox9 is not specific to chondrocytes and can be found in Sertoli cells and can generate insulin-producing β-cells from stem cells in the pancreas"

How does cartilage grow?

A cartilage growth mixture model with collagen remodeling: validation protocols.

"New stress constitutive equations for the solid matrix are derived and collagen (COL) remodeling is incorporated into the CGM model by allowing the intrinsic COL material constants to evolve during growth. An analytical validation protocol based on experimental data from a recent in vitro growth study is developed. Available data included measurements of tissue volume, biochemical composition, and tensile modulus for bovine calf articular cartilage (AC) explants harvested at three depths and incubated for 13 days in 20% fetal borine serum (FBS) and 20% FBS+beta-aminopropionitrile. The proposed CGM model can match tissue biochemical content and volume exactly while predicting theoretical values of tensile moduli that do not significantly differ from experimental values. Also, theoretical values of a scalar COL remodeling factor are positively correlated with COL cross-link content, and mass growth functions are positively correlated with cell density. The results suggest that the CGM model may help us to guide in vitro growth protocols for AC tissue via the a priori prediction of geometric and biomechanical properties."

"The extracellular solid matrix (SM) of AC contains proteoglycans (PGs) and a crosslinked collagen (COL) network"<-this is true of growth plate cartilage as well.

"The PGs are aggregate molecules containing glycosaminoglycans (GAGs) that provide the tissue with a fixed charge density (FCD) that causes a swelling pressure that resists compressive loading"<-the hydrostatic pressure in the AC increases in response to compressive loading.  The growth plate cartilage is constantly compressed by two parts of bone so it has a high hydrostatic pressure there.  Bone does not have these GAGs so it does not have the manipulate fixed charge density to alter hydrostatic pressure.  Therefore it makes sense for bone to generate GAGs(and the chondrocytes to create them) in response to dynamic loading and hydrostatic pressure.

"The crosslinked COL network resists the PG swelling pressure and provides the tissue with both tensile and shear stiffnesses and strengths"

Bioengineering cartilage growth, maturation, and form.

"The growth of cartilage may arise nonuniformly in distinct regions of the tissue through specific biologic activities of the indwelling cells termed chondrocytes[so stem cells that differentiate into chondrocytes could grow cartilage growth plates]. These cells are embedded in a highly hydrated extracellular matrix consisting predominantly of collagen type II and aggrecan, a large, negatively charged proteoglycan. Growth may be mediated through increases in either the cell volume fraction by proliferation or hypertrophy or in the matrix volume fraction by a net accretion of constituent molecules. Early in cartilage development, the tissue is highly cellular, so significant changes in cell number or volume would likely have proportional effects on the tissue volume. As sources of matrix secretion, chondrocytes at high density would also be well poised to contribute to growth through their anabolic production of matrix molecules. However at later stages of growth, chondrocyte density is reduced , and the capacity for further growth is diminished[so proliferative capacity may be related to chondrocyte density, keep chondrocyte density high and keep growing taller]."

In the study, they recommend IGF-1 and BMP-7 as a way to increase cartilage size.