Regarding microcracks being involved in bone length growth via LSJL(Lateral Synovial Joint Loading) Hiroki Yokota writes, "Regarding microcracks, no data [was collected in any of the stuides]. It is interesting if any accumulation of microcracks activates proliferation/differentiation of cells in the growth place. It seems that particular cells in the growth plate are affected by this loading modality[by which he refers to LSJL]."
With such small loads being used it is unlikely for microcrack induction in any case.
But in regards to Growth Plate fusion and the possibility of chondrocyte proliferation/differentation in adults:
Epiphyseal fusion in the human growth plate does not involve classical apoptosis.
"By the end of puberty, growth ceases and epiphyseal fusion occurs through mechanisms not yet completely understood. Human growth plate tissues were collected in various pubertal stages including a unique late pubertal growth plate, which was about to fuse. Apoptosis was studied by TUNEL staining, immunolocalization of pro- and antiapoptotic proteins, and electron microscopy (EM). Morphologic analyses of the fusing growth plate revealed disorganized, large chondrocytes surrounded by a border of dense, cortical-like bone. In the unfused growth plates, few chondrocytes were TUNEL positive. In contrast, the fusing growth plate contained no single TUNEL-positive cell. Antiapoptotic (Bcl-2 and Bcl-XL) and proapoptotic (Bax, Bad, and cleaved caspase-3) proteins were detected in all growth plate zones without change in intensity during pubertal progression. Expression of antiapoptotic proteins was found in the fusing growth plate but of the proapoptotic proteins only Bad was detected. EM revealed no typical signs of apoptosis or autophagy in any of the growth plates. In contrast, morpohological signs of hypoxia and necrosis were observed. We conclude that classical apoptosis is not likely to be involved in the process of human growth plate fusion."
Apoptosis refers to programmed cell death. Autophagy refers to cell degredation. Hypoxia refers to a lack of oxygen. Necrosis is any unnatural death of a cell. Chondrocytes died from hypoxia and necrosis. Since chondrocytes died of unnatural causes this means that anti-oxidants are very good at increasing height during development by preventing some of these unnatural deaths. Note that chondrocyte cell death is indepedent of what induces chondrocyte senescence(they stop dividing).
In the growth plates of the mice in the study "Lengthening of mouse hindlimbs with joint loading" the difference between the loaded and unloaded joints is insane! There are much more chondrocytes and they are much larger. All three of the proliferative zone, the hypertrophic zone, and the overall height of the growth plate increased. The overall height of the growth plate increased create significantly by about 10-15micrometers! What is also interesting is that the total length increase in the growth plate is greater than that in the proliferative and hypertrophic zone! Which suggests that the lengthening is partially as a result of increased levels of Extracellular Matrix(which can increase growth plate height independent of the number of cells). The study does not say for sure what other regions are affected but it speculates that the regions are the resting and calcifying zones.
However, the study states that both lateral and contra-lateral bones(the unloaded bone) increased in length which suggests some sort of mechanical signaling effect.
Growth plates can be 'stretched' and 'compressed' likely as a result of matrix deformation, it is also likely that the distraction of the ECM is involved in height growth. Maybe it's the ECM that actually increases height and not hypertrophic chondrocytes:
Here's a study that suggests that chondrocytes undergo autophagy. There has to be force exerted by chondrocyte activities to actually push the bone apart or otherwise the bone would not elongate during endochondral ossification and just transform from cartilage into bone. Water may be involved as cartilage differs from bone in that it is hydrophillic. But could autophagy of chondrocytes exert forces on the microenvironment resulting in a taller bone?
Autophagy: a new phase in the maturation of growth plate chondrocytes is regulated by HIF, mTOR and AMP kinase.
"We show that in the postmitotic maturing zone of the growth plate, chondrocytes express an autophagic phenotype. This robust and particulate immunohistochemical response provides direct evidence that autophagy is a new and transient stage in the chondrocyte maturation pathway. We found that induction of autophagy was regulated by mTOR, a sensor of cellular metabolism. When mTOR was inhibited, changes in LC3 fluorescence indicated that this kinase regulated development of the autophagic state. To determine if AMP kinase was required for chondrocyte autophagy, we suppressed its expression in N1511 cells using siRNA technology. When these cells were serum starved, a condition that triggers autophagy, there was no change in LC3 distribution. This result confirmed that AMP kinase was required for the induction of the autophagic response. Based on the 2 studies described above, and our previous observation that HIF-1 is required for the induction of autophagy[so if oxygen levels are sufficient enough, autophagy won't occur?], we put forward the hypothesis that autophagy is regulated by the activities of AMP kinase and mTOR in a HIF-1-dependent manner. Once autophagy is activated, the postmitotic chondrocytes would be expected to remain viable in their unique microenvironment and complete their life cycle[so autophagy does not compete with apoptosis but maintains cellular viability until apoptosis]."
"Oxygen tension in the cartilage is low, and hence chondrocytes generate much of their metabolic energy through anaerobic glycolysis. We have argued that the environment may also activate an autophagic response in the maturing cells, which serves to maintain chondrocyte viability until the induction of the apoptosis"<-But will endochondral ossification function properly if autophagy is not initiated due to low oxygen levels?
"autophagic response is seen in many cell types and serves a physiologic role in generating energy utilizing the cells’ own protein and lipid stores"<-this energy could be used to put a distraction force on the bone making it longer.
Endochondral growth in growth plates of three species at two anatomical locations modulated by mechanical compression and tension.
"Sustained mechanical loading alters longitudinal growth of bones, and this growth sensitivity to load has been implicated in progression of skeletal deformities during growth. The objective of this study was to quantify the relationship between altered growth and different magnitudes of sustained altered stress in a diverse set of nonhuman growth plates. The sensitivity of endochondral growth to differing magnitudes of sustained compression or distraction stress was measured in growth plates of three species of immature animals (rats, rabbits, calves) at two anatomical locations (caudal vertebra and proximal tibia) with two different ages of rats and rabbits. An external loading apparatus was applied for 8 days, and growth was measured as the distance between fluorescent markers administered 24 and 48 h prior to euthanasia. An apparently linear relationship between stress and percentage growth modulation (percent difference between loaded and control growth plates) was found, with distraction accelerating growth and compression slowing growth. The growth-rate sensitivity to stress was between 9.2 and 23.9% per 0.1 MPa for different growth plates and averaged 17.1% per 0.1 MPa. The growth-rate sensitivity to stress differed between vertebrae and the proximal tibia (15 and 18.6% per 0.1 MPa, respectively). The range of control growth rates of different growth plates was large (30 microns/day for rat vertebrae to 366 microns/day for rabbit proximal tibia)."
A linear relationship between stress and the percentage of growth modulation suggests a stretching of the growth plates(distraction). If it was mechanical one would expect more diminishing returns. The other implication is of course that compression can decrease bone length and therefore height. But what bone giveth it cannot take it awayth(via the growth plate at least). And any amount of growth stimulation for any period of time should result in an increase of overall body height as once the bone becomes fully formed it is very hard to be taken away.
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