Is it possible to grow taller via articular cartilage?

Unlike most bones which are totally covered by the periosteum, the long bones of the human body only contain periosteum on the sides of the bones while they have articular cartilage on the top.  If it were possible to increase the size of this articular cartilage, it would result in additional body height.

According to wikipedia: "Cartilage has limited repair capabilities, because chondrocytes are bound in lacunae, they cannot migrate to damaged areas "

But, "acute traumatic osteochondral lesions or surgically created lesions extending into subchondral bone by [for example] microfracture [causes] the release of pluripotent mesenchymal stem cells from the bone marrow, may heal with repair tissue consisting of fibrous tissue, fibrocartilage or hyaline-like cartilage."

"Blood and bone marrow (which contains stem cells) seep out of the fractures, creating a blood clot that releases cartilage-building cells."

This implies however that it is necessary to cause a microfracture severe enough to perforate the bone such that blood may flow out.  However, the key ingredient seems to be the stem cells and there is no reason that the blood cannot come from other sources(the body is filled with blood).  Even if the microfractures are not caused directly in the knee area as performed via the microfracture surgery it is still possible for any bone marrow release caused by a microfracture to be caught in the articular cartilage and through that build up to eventually stimulate cartilage growth.

It may be possible for this articular cartilage to be transformed into calcified cartilage and build up bone and height that way.

In Vitro Calcification of Immature Bovine Articular Cartilage Formation of a Functional Zone of Calcified Cartilage

"The zone of calcified cartilage (ZCC) anchors articular cartilage (AC) to subchondral bone through a layer of intermediate stiffness[So it may be possible to get some of that calcified cartilage to ossify into subchondral bone]. The regulation and functional consequences of cartilage calcification may vary with depth from the articular surface. The hypothesis of this study was that the in vitro calcification of immature AC occurs selectively in the deep region and is associated with a local increase in stiffness.
AC and growth plate cartilage (GPC) from calves were incubated in DMEM, 1% fetal bovine serum, 100 µg/mL ascorbate, and ±10 mM β-glycerophosphate (βGP) for up to 3 weeks. To assess the time course and effects of cell viability and βGP, full-depth strips of AC and GPC were analyzed by histology, indentation, and ⁴⁵Ca⁺⁺ uptake. To assess the effect of tissue zone, disks harvested from surface and deep zone AC and from reserve and hypertrophic zone of GPC were incubated independently and analyzed by compression and for ⁴⁵Ca⁺⁺ uptake and biochemical components.
The deep ~20% of immature AC calcified within 3 weeks, with calcification dependent on cell viability and βGP[B-Glycerophosphate may be something worth looking into in regards to height growh]. Mineral was deposited continuously around cells in AC but only between cell columns in GPC{The columnar nature of growth plate chondrocytes may be important, but also it could be dependent on the amount of extracellular matrix}. The deep zone of AC exhibited a compressive modulus of 0.53 MPa after βGP-induced calcification, ~4-fold stiffer than AC incubated without βGP.
Cartilage explants exhibit inherent zone-specific calcification processes, resulting in an increase in stiffness associated with cartilage calcification. Such properties may be useful for engineering a biomimetic ZCC tissue to integrate cartilaginous tissue to bone, thereby forming a mechanically functional osteochondral unit{If we can get this to happen naturally we can grow taller!}."

"The ZCC is 100- to 300-μm thick and is bound on one side by the tidemark, the gently undulating interface with uncalcified cartilage, and on the other side by the cement line, the highly interdigitated interface with subchondral bone."

"In the lower hypertrophic zone, calcification initiates in the territorial matrix close to chondrocytes and spreads throughout the matrix of the longitudinal septa between columns of lower hypertrophic chondrocytes."

"Chondrocytes from the superficial zone secrete soluble factors that can inhibit mineralization by deep zone chondrocytes during in vitro co-culture"<-manipulation of these soluble factors may be a way to manipulate height growth.

"In AC, enlarged chondrocytes and calcified matrix were localized to the deep ~25% of AC. "<-The calcification process may be important to chondrocyte hypertrophy.

Here's a picture compariing growth plate cartilage and articular cartilage:

The stacking of chondrocytes into columns is a key factor that proceeds ossification into bone and may be one of the reasons why articular cartilage doesn't fully ossify.  It also means that chondrocytes don't have to be wholly organized into later in the ossification process.

"Unlike monolayer chondrocyte cultures, which are subject to dedifferentiation and may have effects on cell hypertrophy and mineralization, explant cultures maintain the chondrocyte phenotype because the cells remain within their native extracellular matrix. "<-chondrocyte dedifferentiation may be a problem with LSJL unless sufficient extracellular matrix is secreted by the freshly differentiated chondrocytes.

Zone-specific gene expression patterns in articular cartilage.

"Articular cartilage was obtained from knees of 4 normal human donors[one female (age 23) and three male (age 24, 44 and 46) donors]. The cartilage zones were dissected on a microtome. RNA was analyzed on human genome arrays. Data obtained with human tissue were compared to bovine cartilage zone specific DNA arrays. Genes differentially expressed between zones were evaluated using direct annotation for structural or functional features, and by enrichment analysis for integrated pathways or functions. The greatest differences were observed between SZ and DZ in both human and bovine cartilage. The MZ was transitional between the SZ and DZ and thereby shared some of the same pathways as well as structural/functional features of the adjacent zones. Cellular functions and biological processes enriched in the SZ relative to the DZ, include most prominently ECM receptor interactions, cell adhesion molecules, regulation of actin cytoskeleton, ribosome-related functions and signaling aspects such as Interferon gamma, IL4, CDC42Rac and Jak-Stat. Two pathways were enriched in the DZ relative to the SZ, including PPARG and EGFR/SMRTE."

"The superficial zone (SZ) spans the first 10-20% of full thickness articular cartilage and contains densely packed collagen fibrils and low levels of aggrecan, although fibril associated decorin and biglycan are found in higher concentrations in the SZ. Chondrocytes in this zone produce little PCM, are elongated, flattened and are oriented parallel to the cartilage surface. Cells within the SZ synthesize and secrete the important joint lubricant superficial zone protein (SZP), which is also known as megakaryocyte-stimulating factor, lubricin, or PRG4"

"Clusterin, a glycoprotein that regulates complement activation and cell death is also exclusively expressed in SZ chondrocytes. Chondrocytes located in the SZ differ from DZ chondrocytes by their lower collagen type II gene expression levels, lower production of keratan sulfate and other proteoglycans. The SZ of mature articular cartilage contains cells with phenotypic and functional properties of mesenchymal stem or progenitor cell populations"  The stem cells there express CD105, CD166, Notch-1, STRO-1 and VCAM-1."

"SZ cells are strongly positive for alpha smooth muscle actin, a contractile actin isoform that is also present in progenitor cells"

"The middle zone (MZ) or transitional zone comprises the next 40-60% of cartilage thickness and contains randomly organized collagen fibrils, high concentrations of aggrecan, hyaluronic acid, dermatan sulfate and collagen type II"

"The deep or radial zone contains ellipsoid cells with an extensive PCM amongst radially orientated collagen fibrils that extend into the calcified zone to preserve cartilage and bone integration. In the calcified zone, which represents the boundary between cartilage and subchondral bone, cells are contained within a calcified matrix and express hypertrophic molecules such as collagen type X, alkaline phosphatase (ALP) and osteocalcin"

"increased turnover or activity of ribosomes [may occur] in SZ cells"

Genes upregulated in superficial zone(versus middle zone and deep zone) and in human cartilage also upregulated in LSJL{in italics if regulation differs in LSJL}:

VCAM1{down}

SULF1

MMP2

THBS4

MAMDC2

HHIP

DPT

CAPN6

CDH13

OGN{down}

DOK5

ASPN

SETBP1{down}

LAMA4

EGR2

TNC{down}

Genes downregulated in superficial zone:

Fat1{up}

MFAP3L

VAV3

BSP{up}

Genes upregulated in middle zone:

Genes upregulated in deep zone:

BSP

VAV3{down}

PDE7A{down}

Genes downregulated in deep zone versus other zones:

ASPN{up}

OGN

Col12a1{up}

LSJL gene expression shares the most gene expression similarities with the superficial zone of articular cartilage.

This next study suggests that remodeling of articular cartilage can occur via endochondral ossification into the subchondral bone.  However, why doesn't this remodeling increase height as in the growth plate?

The vascularity and remodelling of subchondrial bone and calcified cartilage in adult human femoral and humeral heads. An age- and stress-related phenomenon.

"A quantitative study of the vascularity and a qualitative study of the remodelling of the calcified cartilage and subchondral bone end-plate of adult human femoral and humeral heads were performed with respect to age. In the femoral head the number of vessels per unit area was found to fall 20% from adolescence until the seventh decade and in the humeral head 15% until the sixth decade. Thereafter an increase was noted in the femur but none in the humerus. More vessels were present at all ages in the more loaded areas of the articular surfaces: 25% more for the femur and 15% more for the humerus. The degree of active remodelling by endochondral ossification declined 50% from adolescence until the seventh decade in the femoral head, and 30% until the sixth decade in the humeral head, rising thereafter to levels comparable to those found at young ages. More remodeling was noted in the more loaded areas at all ages."

If you look at fig 5 you can see subchondral bone resorbing calcified cartilage so a kind of endochondral ossification does sort of occur.

"Lemper, who studied subchondral bone plate remodelling in rabbits by microradiography and tetracycline labelling, demonstrated that remodelling, which occurs at a very rapid rate in immature rabbits, continues at a slower rate after the termination of longitudinal growth. In a study of the adult human patella Green, Martin, Eanes, and Sokoloff (1970) concluded that “continuous growth activity goes on in the osteochondral region during the adult years”."

"the osteochondral ends of bone probably remodel as a result of vascular invasion and enchondral ossification of the calcified cartilage, "

"It can be seen that a group of cartilage-cells upon reaching the margin of the (subchondral) bone . . . becomes converted into one of (its) prominences"

Role of endochondral ossification of articular cartilage and functional adaptation of the subchondral plate in the development of fatigue microcracking of joints.

"Endochondral ossification of articular cartilage and modeling/remodeling of the subchondral plate and epiphyseal trabeculae are important components of the adaptive response. We performed a histologic study of the distal end of the third metacarpal/metatarsal bone of Thoroughbreds after bones were bulk-stained in basic fuchsin and calcified sections were prepared. The Thoroughbred racehorse is a model of an extreme athlete which experiences particularly high cyclic strains in distal limb bones. The following variables were quantified: microcrack boundary density in calcified cartilage (N.Cr/B.Bd); blood vessel boundary density in calcified cartilage (N.Ve/B.Bd); calcified cartilage width (Cl.Cg.Wi); duplication of the tidemark; and bone volume fraction of the subchondral plate (B.Ar/T.Ar). Measurements were made in five joint regions (lateral condyle and condylar groove; sagittal ridge; medial condylar and condylar groove). N.Cr/B.Bd was site-specific and was increased in the condylar groove region; this is the joint region from which parasagittal articular fatigue (condylar) fractures are typically propagated. Formation of resorption spaces in the subchondral plate was co-localized with microcracking. N.Ve/B.Bd was also site-specific. In the sagittal ridge region, N.Ve/B.Bd was increased, Cl.Cg.Wi was decreased, and B.Ar/T.Ar was decreased, when compared with the other joint regions. Multiple tidemarks were seen in all joint regions. Cumulative athletic activity was associated with a significant decrease in B.Ar/T.Ar in the condylar groove regions. N.Cr/B.Bd was positively correlated with B.Ar/T.Ar (P < 0.05, r(s) = 0.29) and N.Ve/B.Bd was negatively correlated with B.Ar/T.Ar (P < 0.005, r2 = 0.14) and Cl.Cg.Wi (P < 0.05, r2 = 0.07). endochondral ossification of articular cartilage and modeling/remodeling of the subchondral plate promote initiation and propagation of site-specific fatigue microcracking of the joint surface, respectively, in this model. Microcracking of articular calcified cartilage likely represents mechanical failure of the joint surface. Propagation of microcracks into the subchondral plate is a critical factor in the pathogenesis of articular condylar fatigue (stress) fracture. Functional adaptation of the joint likely protects hyaline cartilage from injury in the short-term but may promote joint degeneration and osteoarthritis with ongoing athleticism."

"Loading does not have to be great to induce microcracking, if it is rapidly applied"

"bone may not effectively resist propagation of microcracking, especially if abnormal or atypical loads are applied"

If you look at figure 4, you can see "In-growth of blood vessels into the calcified cartilage layer was a prominent feature seen in all joint regions but was increased in the sagittal ridge region"

"Microcracking always involved the calcified cartilage. Within the condylar grooves, short microcracks located within the calcified cartilage were typically co-localized with in-growth of a blood vessel into calcified cartilage. Longer microcracks extended proximally into the bone of the subchondral plate"

"Microcracking is co-localized with in-growth of blood vessels from the subchondral plate into the calcified cartilage"

"the subschondral bone spares cartilage from load done at the joint surface."  Remodeling of the subchondral may proceed changes to the articular cartilage.

"mechanisms that induce microcracking of calcified cartilage and in-growth of blood vessels into calcified cartilage are different. In-growth of blood vessels into the condylar groove calcified cartilage precedes and likely promotes initiation of microcracking of calcified cartilage in regions of the joint that experience particularly high stresses."

"Athleticism in racing Thoroughbreds commonly leads to premature failure of the hyaline articular cartilage, with development of full thickness erosions of the articular cartilage over the axial part of the condyles in the palmar/plantar region of the joint. Another common feature of active endochondral ossification of the joint surface is duplication of the tidemark. We identified duplication of the tidemark as a prominent feature in all regions of the joint. "

"Endochondral ossification of articular cartilage at the ends of long bones like represents functional adaptation to joint loading over time."

"mechanisms that induce microcracking of calcified articular cartilage and ingrowth of blood vessels are likely different"  In growth of blood vessels into calcified cartilage in the condylar groove proceeds and likely initiates calcified cartilage.  Blood vessel ingrowth in the calcified cartilage was associated with a reduction of width of the calcified cartilage layer.

"Microcracking of the articular surface likely represents early mechanical failure of the joint surface to high transarticular loads. In-growth of blood vessels into calcified cartilage promotes site-specific microcracking of calcified cartilage. Functional adaptation of the distal end of the Mc-III/Mt-III bone includes active endochondral ossification of the epiphyseal articular cartilage which may improve joint congruity, sclerosis of epiphyseal trabecular bone, and active remodeling and progressive loss of bone mass from the superficial region of the subchondral plate.  a common mechanism activates endochondral ossification of the joint surface and functional adaptation of the subchondral plate."

Type X collagen is upregulated by LSJL but not by axial loading.

The role of type X collagen in facilitating and regulating endochondral ossification of articular cartilage.

"There are spatial and temporal correlations between synthesis of type X collagen and occurrence of endochondral ossification. The expression of type X collagen is confined within hypertrophic condrocytes and precedes the embark of endochondral bone formation. Type X collagen facilitates endochondral ossification by regulating matrix mineralization and compartmentalizing matrix components.

Type X collagen is a reliable marker for new bone formation in articular cartilage. The future clinical application of this collagen in inducing or mediating endochondral ossification is perceived, e.g. the fracture healing of synovial joints and adaptive remodeling of madibular condyle."

"The peak of type X collagen mRNA and molecular expression in hypertrophic chondocytes of condylar cartilage occurred before the peak of new bone formation in the erosive cartilage. These finding are fully supportive to the statement that type X collagen expression is closely associated with endochondral ossification and invariably precedes the onset of ossification"

"Condylar cartilage, or the secondary cartilage growth starts with the mesenchymal-like tissue covering of the prenatal or postnatal condyle. The new members of the cartilage family therefore have been added without the mitosis of existing cartilage mother cells, but through mitosis of undifferentiated mesenchymal cells. This mode of growth in which new cells are added from the exterior is appositional growth"

How does articular cartilage differ from GP cartilage?

Early articular cartilage degeneration in a developmental dislocation of the hip model results from activation of β-catenin.

"Developmental dislocation or dysplasia of the hip (DDH) is one of the most common deformities in children. Osteoarthritis (OA) is the most frequent long-term complication. The molecular mechanism of early articular cartilage degeneration in DDH is still unclear. It is well known that β-catenin plays a crucial role in articular cartilage degeneration. The objective of this study was to verify the relationship between β-catenin and DDH cartilage degeneration. We used a DDH model that was established by modification of swaddling position in newborn Wistar rats. The hips were isolated from the DDH model rats and untreated control group at the age of 2, 4, 6 and 8 weeks. β-Catenin gene and protein were investigated by quantitative (q)RT-PCR and immunohistochemistry. Collagen X and matrix metalloproteinase (MMP)-13, markers of early cartilage degeneration, were assessed by qRT-PCR. Primary chondrocytes were cultured from cartilage of two groups at the age of 8 weeks. Expression of β-catenin, collagen X and MMP-13 was detected. Continued high expression of β-catenin was observed in cartilage from DDH model rats. mRNA and protein expression of β-catenin was significantly increased in primary chondrocytes of the DDH model compared with the control group. Collagen X and MMP-13 expression was higher in the cartilage and chondrocytes from DDH model rats than the control group. Our findings suggest that early cartilage degeneration in DDH may result from activation of β-catenin signaling."

"Expression of β-catenin in articular cartilage of control group at different ages. A. 2 weeks; B. 4 weeks; C. 6 weeks; D. 8 weeks. Expression of β-catenin protein decreased with age."

"morphology of articular cartilage in the DDH model differed from that in the control group. Loss of the smooth surface of articular cartilage and aggregates and clusters of articular chondrocytes were detected. "

The hip in DDH actually looks compressed which explains why it wouldn't result in height growth.

Comparison of gene expression profile between human chondrons and chondrocytes: a cDNA microarray study.

"The chondron is a basic unit of articular cartilage that includes the chondrocyte and its pericellular matrix (PCM). This current study was designed to investigate the effects of the chondron PCM on the gene expression profile of chondrocytes.

Chondrons and chondrocytes were enzymatically isolated from human articular cartilage, and maintained in pellet culture. Pellets of chondrons or chondrocytes were collected at days 1, 3 and 5 for cDNA microarray analysis.

In comparison with chondrocytes alone, chondrons had 258 genes, in a broad range of functional categories, either up- or downregulated at the three time points tested. At day 1, 26 genes were significantly upregulated in chondrons and four downregulated in comparison to chondrocytes. At day 3, the number of upregulated chondron genes was 97 and the number downregulated was 43. By day 5, there were more downregulated genes (56) than upregulated genes (32) in chondrons.  (HSPA1A, HSPA2 and HSPA8) [were upregulated] in chondrons. Genes related to chondrocyte hypertrophy and dedifferentiation such as SSP1 and DCN were downregulated in chondrons as compared to the expression in chondrocytes.

The presence of the PCM in chondrons has a profound influence on chondrocyte gene expression. Upregulation of the heat shock protein 70 may contribute to the robustness and active matrix production of chondrons. The intact PCM may further stabilize the phenotype of chondrocytes within chondrons."

"The pericellular “capsule” represents about 60% of the cross-sectional area of chondrons, and is an osmotic buffer zone to the enclosed chondrocytes"

Gene comparison to LSJL to be done.

"The influence of PCM on chondrocytes is continuous, but changes roles. At day 3, most of the significantly regulated genes in chondrons were in the functional categories of metabolism, protein assembly/transport and signaling. By day 5, the most prominent functional group was signaling."

"The upregulation of HSP genes (HSPA1A, HSPA2 and HSPA8) and BAG3, which is a cochaperone partner of HSP29, can be one of the mechanisms that protect chondrons from stresses. On the other hand, the decreased expression of SSP1, expressed by hypertrophic chondrocytes, in chondrons may suggest a reduction of terminal differentiation and apoptosis in the chondron population. "

Histology of epiphyseal cartilage calcification and endochondral ossification

"Cartilage calcification is carried out by chondrocytes as they hypertrophy and begin to secrete matrix vesicles. Calcification initiates when calcium phosphates appear inside these matrix vesicles, forming hydroxyapatite crystals that eventually break through the membrane to form calcifying globules, as in bone calcification. However, the extracellular environment in cartilage is different from that in bone: cartilage is abundant in proteoglycans but contains a small amount of osteopontin. Hypertrophic chondrocytes secrete vesicles in the cartilaginous matrix of intercolumnar septae only, forming well-calcified longitudinal septae and poorly-calcified transverse partitions. Such pattern of vesicle deposition permits the invasion of endothelial cells, which infiltrate into cartilage and induce migration of osteogenic and osteoclastic cells. Osteoclasts resorb the excess of calcified globules in the partitions, shaping calcified cartilage cores paralleling the longitudinal axis of long bones. After the formation of these calcified cartilage cores, endochondral ossification involves a series of well-defined events in which osteogenic cells deposit new bone onto the cartilage core and form primary trabecules.  "

"The extracellular matrices, as an ion reservoir, may constitute the adequate microenvironment for the initiation of calcification. Proteoglycans are complexes of various glycosaminoglycan (GAG) chains and core proteins. The GAG chains are highly negatively charged, which can attract free divalent cations such as Ca2+ . It seems likely that proteoglycans significantly impact the dynamics of the extracellular fluid's mineral ionic content. Since cartilage contains abundant proteoglycans, cartilage matrices may serve as a reservoir for free divalent cations. Especially, crystal ghosts appear to be rich in sulfated GAG chains , especially, chondroitin sulfate"<-So the ECM may signal when calcification occurs.

"proteoglycans in the extracellular matrix of the lower hypertrophic zone may be degraded by proteases and removed before calcification, and this seems to be the mechanism by which a matrix that does not possess the ability to calcify is transformed into one that has that capability. Interestingly, however, the concentration of sulfate or cartilage proteoglycans was not shown to change before and after cartilage calcification"

"epiphyseal chondrocytes may be able to transdifferentiate into osteoblasts, since terminally differentiated chondrocytes were biosynthetically active. These cells have been shown to synthesize osteogenic markers such as type I collagen, glycosaminoglycans, osteopontin, osteocalcin and osteonectin. Therefore, we assumed that chondrocytic apoptosis may depend on genetic programming such as Bcl2 expression, but may also be influenced by other conditions, i.e., intracellular concentration of Pi and nitric oxide generation. We also reported that parathyroid hormone-related peptide deficiency may stimulate chondrocytic apoptosis "

The tidemark of the chondro-osseous junction of the normal human knee joint

"The tidemark represents a calcification front, at which non-mineralised cartilage matrix comes to contain hydroxyapatite"

" though cells were often seen in close apposition to the tidemark, none were observed to be embedded within it. This is consistent with the ultrastructural observations of Bullough & Jagannath that chondrocytes were sometimes partially embedded in the mineralising face of the tidemark, but were not wholly sealed within it. In general, chondrocytes near the tidemark must maintain control over the local matrix and regulate the turnover of non-collagenous components of this matrix. During normal growth and development of diarthrodial joints the tidemark clearly represents a calcification front. In the normal adult joint, the tidemark is still a single structure, but the advance of mineral into the hyaline cartilage has ceased, though a residual ‘maintenance’ turnover of matrix may occur. Under these conditions the tidemark may have ceased to function as a calcification front, though it still contains some tightly bound calcium. It is possible that, at this stage, the tidemark has changed in function to one of inhibiting the formation or growth of microcrystals of hydroxyapatite and so protecting the hyaline cartilage from passive progressive mineralisation. "

Investigation of chondrocyte hypertrophy and cartilage calcification in a full-depth articular cartilage explants model

"Articular cartilage deterioration, which includes cartilage degradation and chondrocyte hypertrophy, is a hallmark of degenerative joint diseases (DJD). Chondrocyte hypertrophy is initiated in the deep layer of the cartilage; thus, a robust explants model for investigation of hypertrophy should include this zone. The aim of this study was to characterize and investigate the hypertrophy-promoting potential of different endogenous factors on an ex vivo articular cartilage model. The full-depth cartilage explants were harvested from bovine femoral condyle and cultured for 13 days in different conditions: 10 ng/ml oncostatin M + 20 ng/ml TNF-α; 100 ng/ml IGF1; 10–100 ng/ml bFGF; 10–100 ng/ml BMP2; 50 μg/ml ascorbic acid in combination with 10 mM β-glycerophosphate; and 20–100 ng/ml triiodothyronine. The cellular activity and morphology, degradation, formation and calcification, and expression level of hypertrophic markers were investigated. The hypertrophic factors tested all induced cellular activity and marked morphological changes starting at day 4, however, not in a synchronized manner. Both cartilage degradation and formation were induced by T3 (P < 0.05). Only T3 had a full hypertrophic gene expression profile (P < 0.05). We developed and characterized a novel model for investigation of chondrocyte hypertrophy. We speculated that this can become an important investigatory tool for investigation of matrix turnover, chondrocyte hypertrophy and cartilage calcification that are associated with DJD pathogenesis."

Finding out how to initiate chondrocyte hypertrophy could be a way to become taller.

" Cartilage calcification is initiated from the subchondral cartilage where chondrocytes undergo hypertrophic differentiation and apoptosis. "<-I'm not sure what is meant by subchondral cartilage.

"The full stage of chondrocyte hypertrophic phenotype was characterized by pre-hypertrophic chondrocytes produced by IHH, COLX synthesized by hypertrophic chondrocytes
and MMP13 related to mature hypertrophic chondrocytes, followed by ALP expression represented by chondrocyte hypertrophy and indicating matrix calcification. We found that several of the factors tested could induce morphological changes that resemble hypertrophy; however, only T3 (20 ng/ml) expressed a pre-hypertrophic and hypertrophic profile. "

Chondrocyte hypertrophy and osteoarthritis: role in initiation and progression of cartilage degeneration?

"Changes in chondrocyte behavior, such as expression of hypertrophy markers and matrix calcification, frequently resemble the phenomena observed in the hypertrophic layer of the growth plate of long bones"

"Temporary hyaline cartilage is found in the embryonic stages of endochondral bones and the growth plate and is finally replaced by bone. Permanent hyaline cartilage, present amongst others in articulating joints, does not undergo terminal differentiation under normal conditions."

"The cellular origin of both types of temporary and permanent cartilage is similar. As concluded from both in vivo and in vitro studies, the default route of chondrocyte differentiation is terminal differentiation (hypertrophy and apoptosis). An enlightening in vivo model of adult chondrocyte differentiation is osteophyte formation. Osteophytes are the result of chondrogenic differentiation of mesenchymal stem cells in the periosteum. Initially cartilage is formed but the final product is bone. Apparently, unrestricted differentiation of precursor cells into the chondrocyte lineage does not lead to permanent cartilage but to bone. In articular cartilage, this default route is somehow blocked to obtain permanent cartilage."

"A route that has been proposed[for OA] is that articular chondrocyte loose their differentiated phenotype and obtain a behavior with similarities to terminal differentiating chondrocytes (hypertrophy-like), as can be found in the growth plate of growing individuals"

"osteopontin, osteocalcin, Indian Hedgehog, Runx2, VEGF, HtrA1 and transglutaminase-2 (TG-2) are all shown to be associated with chondrocyte hypertrophy. However, one has to keep in mind that, although accepted as a hypertrophy marker, MMP13 synthesis is induced in chondrocytes by alternative routes, such as inflammation and mechanical stress"

"Calcification of articular cartilage and ossification as a result of terminal differentiation of chondrocytes might be different processes, but a number of studies have indicated overlapping phenomena. Studies in the sixties and seventies of the last century have shown that in human cartilage the number of tidemarks, the line bordering the calcified cartilage and the non-calcified cartilage, is increased above the age of 60. This movement of the tidemark to the cartilage surface should result in an increase in the thickness of the calcified cartilage, but it is shown that instead the calcified zone becomes thinner during aging. This indicates replacement of the lower calcified cartilage by bone because of endochondral ossification."

"OA is related to ossification processes in articular cartilage. Next to increased alkaline phosphates and pyrophosphate levels, calcification is a common observation in OA. Not only in large joints, but also degenerative changes in intervertebral discs have been associated with tissue calcification"

"Hypertrophic chondrocytes in the growth plate do not only express specific molecules such as type X collagen, but also undergo apoptosis to make bone deposition possible. Apoptosis can be considered as a marker for chondrocyte hypertrophy in OA cartilage"