Friday, December 20, 2013

Case(s) of adult bone length growth








Metacarpophalangeal length changes in humans during adulthood: A longitudinal study

Metacarpophalangeal refers to hand bones essentially.


The increase in bone length was about 0.34 mm per decade.







Continuing bone growth throughout life: A general phenomenon



The scientists reported an increase in skull length.

"Modeling-based bone formation contributes to the periosteal expansion, just as remodeling-based resorption is responsible for the medullary expansion seen at the long bones with aging."<-Can we translate this into height?

"Odanacatib inhibits bone resorption by inhibiting cathepsin K activity, whereas modeling-based bone formation is stimulated at periosteal surfaces. Inhibition of sclerostin stimulates bone formation and histomorphometric analysis demonstrated that bone formation is predominantly modeling based."

"Strain alone can induce a significant increase in bone morphogenetic protein 2 (BMP2) mRNA levels in human BM-MSPCs without any addition of osteogenic supplements"

" Excessive strain causes regional microdamage, which leads to targeted remodeling removing the damaged bone and a larger volume of the surrounding undamaged bone, this temporary volume deficit increases the strain in neighboring bone and the potential establishment of a vicious cycle between damage and repair"

"Bone modeling has been demonstrated in aging humans. Modeling-based bone formation contributes to the periosteal expansion, just as remodeling-based resorption is responsible for the medullary expansion seen at long bones and ribs with aging"

"Osteocytes are terminally differentiated osteoblasts which become embedded in newly formed bone matrix and produce sclerostin. Sclerostin binds to lipoprotein-related peptide (LRP) 5/6 and thereby inhibits LRP5/6 from binding to the frizzled receptor and activating the Wnt pathway"











Mechanical strain leads to condylar growth in adult rats.
















Here's the picture of experimental jaw versus control:


Here's the ectopic chondrogenesis highlighted with GIMP(blue line):

Here's the Col2a1 expression areas:


Forward mandibular positioning enhances condylar adaptation in adult rats.


The rats were advanced 4 mm in continuous advancement.  I don't know exactly what this means.




If you look at figure 5 you can see the new bone formation.

If you look at figure 6, it took until about day 21 to start seeing results and results decreased at day 60 so there could be an adaptive mechanism.

It would be interesting to note if intermittent mandibular forward positioning could result in the same objective.

"case of altered condylar morphology in adult male with temporomandibular disorders was reported in 30-year-old male patient. Erosion and flattening of the left mandibular condyle were observed by panoramic x-ray. The patient was treated with splint therapy that determined mandibular advancement. Eight months after the therapy, reduction in joint pain and a greater opening of the mouth was observed, although crepitation sounds during mastication were still noticeable."

"The mandibular condyle is an ovoidal bony structure that articulates with the temporal bone by means of a biconcave disk."

"Both articular surfaces are covered by a connective fibrous tissue (condylar cartilage). On the articular surface of the condyle, the collagen fibres are parallel to the condylar surface, and are in continuity with the fibrous layer of the periosteum.

The condylar cartilage covers very dense undifferentiated mesenchyme, within which are multipotential cells, forming either cartilage or bone, depending upon the environmental circumstances"<-the presence of this mesenchyme may not be present in other regions.

"Mandibular condylar cartilage is characterised histologically as fibrocartilage containing a layer of pre-chondroblastic mesenchymal stem cells which can undergo rapid differentiation into chondrocytes.

Other forms of mature articular cartilage do not have such progenitor cells and only poorly responsive chondrocytes "<-this is a problem.  Though I do not think this is entirely true.
"subcondylar trabecular bone formation is apparently not affected by age"<-The study mentioned is 

Induced growth of the mandibular condyle in the rat

"Advancement of the calcification front in the cartilage, which is a measure of the growth of the cartilage, can be determined by the administration of two dose bone‐markers at specific intervals. It appears that growth still takes place in animals of 12–18 months. This growth is possible by the persistence of chondrogenic cells. The overall growth of the central part of the condyle amounts to about 2 mm over the period from 2 to 18 months.

Raising of the bite in the rat has an obvious influence on the temporomandibular joint, and on the condyle in particular. Within a few days an increase of growth‐rate of cartilage can be demonstrated. This extra growth is temporary, and the intensity and duration of the response is determined by the age of the animal. This adaptation is related to the presence of chondrogenic cells in the cartilaginous layer in the condyle."

"From the results it can be seen that an increase of the vertical dimension leads to a temporary period of extra growth of the condyle. Not only is the chondrogenic zone activated but the cartilaginous zone also reacts with heightening of its layer by production of cartilaginous substance

Effects of mechanical loads on surface morphology of the condylar cartilage of the mandible in rats.,  "Hard-diet condyles had a rougher, more porous articular surface while soft/hard-diet condyles were intermediate between nonporous and slightly roughened condyles. None of the condyles showed ridges or elevations on the articular surface. Sex, age and time of the diets did not significantly affect these results."

Cell and matrix response of temporomandibular cartilage to mechanical loading.

"The generation of transgenic mice expressing green fluorescent proteins (GFPs) has greatly aided our understanding of the development of connective tissues such as bone and cartilage. Perturbation of a biological system such as the temporomandibular joint (TMJ) within its adaptive remodeling capacity is particularly useful in analyzing cellular lineage progression. The objectives of this study were to determine: (i) if GFP reporters expressed in the TMJ indicate the different stages of cell maturation in fibrocartilage and (ii) how mechanical loading affects cellular response in different regions of the cartilage.
Four-week-old transgenic mice harboring combinations of fluorescent reporters (Dkk3-eGFP, Col1a1(3.6 kb)-GFPcyan, Col1a1(3.6 kb)-GFPtpz, Col2a1-GFPcyan, and Col10a1-RFPcherry) were used to analyze the expression pattern of transgenes in the mandibular condylar cartilage (MCC). To study the effect of TMJ loading, animals were subjected to forced mouth opening with custom springs exerting 50 g force for 1 h/day for 5 days. Dynamic mineralization and cellular proliferation (EdU-labeling) were assessed in loaded vs control mice.
Dkk3 expression was seen in the superficial zone of the MCC, followed by Col1 in the cartilage zone, Col2 in the prehypertrophic zone, and Col10 in the hypertrophic zone at and below the tidemark. TMJ loading increased expression of the GFP reporters and EdU-labeling of cells in the cartilage, resulting in a thickness increase of all layers of the cartilage. In addition, mineral apposition increased resulting in Col10 expression by unmineralized cells above the tidemark.
The TMJ responded to static loading by forming thicker cartilage through adaptive remodeling."

"Unlike most hyaline articular cartilages in the appendicular joints, the MCC is classified as fibrocartilage "

"new mineralized cartilage apposition within the 24-hour period"

If you look at figure 3 you can see signs of increased endochondral ossification.

"The TB signal extended into in the mineralized cartilage zone and protruded further into the subchondral bone in the loaded group."

"loading enhances the accumulation of mineralized cartilage resulting in a greater separation of the unmineralized cartilage from the subchondral bone."<-this seems to indicate that maybe endochondral ossification did not occur.  And only cartilage mineralization.

Biomechanical behavior of the temporomandibular joint disc.
"The temporomandibular joint (TMJ) disc consists mainly of collagen fibers and proteoglycans constrained in the interstices of the collagen fiber mesh. This construction results in a viscoelastic response of the disc to loading and enables the disc to play an important role as a stress absorber during function. The viscoelastic properties depend on the direction (tension, compression, and shear) and the type of the applied loading (static and dynamic). The compressive elastic modulus of the disc is smaller than its tensile one because the elasticity of the disc is more dependent on the collagen fibers than on the proteoglycans. When dynamic loading occurs, the disc is likely to behave less stiffly than under static loading because of the difference of fluid flow through and out of the disc during loading. In addition, the mechanical properties change as a result of various intrinsic and extrinsic factors in life such as aging, trauma, and pathology. Information about the viscoelastic behavior of the disc is required for its function to be understood and, for instance, for a suitable TMJ replacement device to be constructed. In this review, the biomechanical behavior of the disc in response to different loading conditions is discussed"

"The articular surfaces of the TMJ are highly incongruent. Due to this incongruence, the contact areas of the opposing articular surfaces are very small. When joint loading occurs, this may lead to large peak loads, which may cause damage to the cartilage layers on the articular surfaces. The presence of a fibro-cartilaginous disc in the joint is believed to prevent these peak loads since it is capable of deforming and adapting its shape to that of the articular surfaces. These deformations ensure that loads are absorbed and spread over larger contact areas. In addition, the shape of the disc and the area and location of its contact areas with the articular surfaces change continuously during jaw movement to adapt to the changing geometry of the articular surfaces of the mandible and temporal bone."

" while translation of the condyle in the forward direction to obtain a protrusive or open jaw position leads to a concentration of the deformation in the lateral part of the disc."

"When the disc is compressed or stretched in one direction, not only will it deform in that direction (primary strain), but it will also become thicker or thinner, respectively, in a direction perpendicular to it (secondary strain). "

"the small permeability of the collagen network impedes interstitial fluid flow through this network. Therefore, the loads acting on a cartilaginous structure as the disc are initially transmitted by a pressurization of the incompressible fluid without much deformation of the collagen network. Nonetheless, fluid flow through the collagen network leads to a gradual transfer of the load from the fluid to the collagen fibers. When further loaded, the collagen network deforms, and water is squeezed out of the disc while the orientation of the collagen fibers is re-arranged "

"The movement of fluid out of the disc and the re-arrangement of the collagen fibers are reversible when the disc is not deformed beyond the physiologic strain range. Even application of significant long-term stresses beyond the physiologic strain range introduces but minor changes in fiber waviness and alignment within the disc. This enables the disc to adapt its shape continuously to fit in the space between the opposing articular surfaces and to distribute loads suitably in the TMJ. Collagen gives the disc much of its tensile stiffness and strength. "

"mechanical stress affects the GAG synthesis in the disc, especially that of chondroitin sulfate, dermatan sulfate, and hyaluronic acid. Static loading decreases the proteoglycan synthesis in cartilaginous structures, whereas dynamic loading is positively related to this synthesis and is considered as an important factor for maintenance of the homeostasis of the joint cartilage "<-maybe because dynamic loading drives fluid flow and allows more nutrients to get in?

Here's a study on how progenitor cells in the cartilage may play a role in this process:

Progenitor Cells of the Mandibular Condylar Cartilage.
"The secondary cartilage of the mandibular condyle is unique as it undergoes endochondral ossification during growth and robustly remodels in response to changes in its mechanical loading environment. This cartilage is derived from mesenchymal progenitor cells that express markers of early osteoblast differentiation, namely alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2). Interestingly, these progenitor cells then differentiate into cartilage with appropriate mechanical loading. Our laboratory has determined that these cells can be labeled by osteoblast progenitor cell markers, including the 3.6 fragment of the rat collagen type 1. However, the role these mesenchymal progenitor cells play in adult mandibular condylar cartilage maintenance and adaptation, as well as the existence of a more potent progenitor cell population within the mandibular condylar cartilage, remain in question. Further characterization of these cells is necessary to determine their potency and regenerative capacity to elucidate their potential for regenerative therapy."

"After the cessation of growth, the mandibular condylar cartilage becomes phenotypically similar to other articular cartilages by entering into a post-mitotic state"

"there still appears to be a progenitor cell population capable of reactivating in response to changes in mechanical loading"<-where these progintor cells are present in other articular cartilage is the question.

Progenitor cells in other articular cartilage types:

Origin and function of cartilage stem/progenitor cells in osteoarthritis.

"Articular cartilage is a physiologically non-self-renewing avascular tissue with a singular cell type, the chondrocyte, which functions as the load-bearing surface of the arthrodial joint. Injury to cartilage often progresses spatiotemporally from the articular surface to the subchondral bone, leading to development of degenerative joint diseases such as osteoarthritis (OA). Although lacking intrinsic reparative ability, articular cartilage has been shown to contain a population of stem cells or progenitor cells, similar to those found in many other adult tissues, that are thought to be involved in the maintenance of tissue homeostasis. These so-called cartilage-derived stem/progenitor cells (CSPCs) have been observed in human, equine and bovine articular cartilage, and have been identified, isolated and characterized on the basis of expression of stem-cell-related surface markers, clonogenicity and multilineage differentiation ability. However, the origin and functions of CSPCs are incompletely understood. We review here the current status of CSPC research and discuss the possible origin of these cells, what role they might have in cartilage repair, and their therapeutic potential in OA."

"mild enzymatic insult to the cartilage ECM promoted CPCs migration in cultured articular cartilage explants."

Superficial cells are self‐renewing chondrocyte progenitors, which form the articular cartilage in juvenile mice

"Articular cartilage has little regenerative capacity. Recently, genetic lineage tracing experiments have revealed chondrocyte progenitors at the articular surface. We further characterized these progenitors by using in vivo genetic approaches. Histone H2B–green fluorescent protein retention revealed that superficial cells divide more slowly than underlying articular chondrocytes. Clonal genetic tracing combined with immunohistochemistry revealed that superficial cells renew their number by symmetric division, express mesenchymal stem cell markers, and generate chondrocytes via both asymmetric and symmetric differentiation. Quantitative analysis of cellular kinetics, in combination with phosphotungstic acid–enhanced micro–computed tomography, showed that superficial cells generate chondrocytes and contribute to the growth and reshaping of articular cartilage. Furthermore, we found that cartilage renewal occurs as the progeny of superficial cells fully replace fetal chondrocytes during early postnatal life. Thus, superficial cells are self‐renewing progenitors that are capable of maintaining their own population and fulfilling criteria of unipotent adult stem cells. Furthermore, the progeny of these cells reconstitute adult articular cartilage de novo , entirely substituting fetal chondrocytes."

<-We need to know how effective these stem cells are at self renewing as adults for adult height increase via articular cartilage.

"whereas deep articular chondrocytes in adult mice are derived from cells that were initially at the cartilage surface in newborn mice, which is consistent with appositional growth, beneath the surface cartilage, growth is also interstitial"

"superficial cells are slow-dividing progenitors of middle and deep zone chondrocytes"

Regional shape change in adult facial bone curvature with age.




