Key:
- downregulate
+ upregulate
-> transcription regulation
+/- means the result is dose or experiment dependent
Okay here's a draft of the genetic regulation involved height growth. We want to focus mainly on the genes that promote chondrogenesis although eventually we'll go through genes that maximize height. These up- and down- regulations may not happen all the time but showed up in at least one study and may be dose and/or environment dependent.
Key factors in initiating height growth seem to be inhibiting the NFKappaB pathway and Runx2. Although this study here shows no effect of Runx2 on bone length. Sox9 and the interplay between TGFBeta1 and BMP2 seem key to initiating a new growth plate. Finding the TGF and BMP Smad interplay will be key in developing therapies to grow taller as will PTH/IHH interplay.
Posting this now to get feedback on genes/interactions I'm missing. Eventually I'll draw a graphic representing the interaction. Also, take note of Harpogoside and Acteoside which inhibit NFKappaB activity. Two supplements that I looked at earlier that take on additional relevance now due to the importance of NFKappaB on height growth.
Also, tomorrow I'll be posting an LSJL finger update.
Sox9 -> Col2a1(intron 1, intron 6)
IL1:
- Sox9
- chondrocyte proliferation
+MMPs
TNFalpha:
-Sox9
FGFs:
+Sox9
-Ihh
PKA+Sox9
S181+Sox9
TGFBeta:
+Sox9
+Aggrecan
+Col2A1
+BMP2
+Smad2/3P
+F-spondin
-cartilage tissue growth(encourages homeostasis)
+Fibronectin
BMPs:
+Ihh
-PTHrP
BMP2:
+Sox9
+Aggrecan
+Col2A1
+Smad1/5/8P
+Beta-Catenin
-TGFBeta1
BMP7:
+cartilage tissue growth
+GAGs
LIPUS:
+BMP2
+FGF7
+TGFBetaR1
+EGFR1
+VEGF
+PI3K
-GSK3Beta
IGF-1:
-RhoA
+cartilage tissue growth
+GAGs
+Twist1
Noggin:
-BMP
-Height
Gremlin:
-BMP
Chordin:
-BMP
Bezafibrate:
+BMP2
+RUNX2
RhoA:
-chondrogenesis
-chondrocyte maturation
+PI3K
Rac1:
-chondrogenesis
+chondrocyte maturation
+alkaline phosphatase
+adhesion
+Col2A1
+Aggrecan
-GAGs
+Sox9
Mechanical Loading:
+TGFBeta1
+IGF-1
LSJL:
+/-MMP3(depends on load)
-MMP1
-MMP8
-MMP13
+hyaluranon synthase 1
+TIMP1
+GAGs
+Interleukin 1 receptor-like 1
-TNF
+TGF-Beta1
+TGF-BetaR1
+Follistatin
+ActivinR1
-EIF2alpha phosphorylation
+CITED2
+Actin filament remodeling
Icariin:
+BMP2
+BMP4
+Cpfalpha1
-COX2
-PGE
PEMF:
+proteoglycans
+ECM
+Col2A1
+/-ALP
+MMP2
+Sox9
+MT1-MMP
+proteoglycan sulfation
-Collagen Type X
FGF:
-Ihh
FGF2:
-cellular senescence
FGFR3:
-height
SUMF1:
+Activate sulfates that catalyze desulfation of the GAGs moiety of proteoglycans in the intracellular and extracellular space.
+ECM
+height
-FGF
CHOP:
+apoptosis
+IL1
+IL6
AKT1:
-caspase3
+BclXL
+chondrocyte survival
Salubrinal:
+EIF2alpha phosphorylation
+ATF3
+ATF4
+Chop
-Cell death
Mechanical Loading:
Alteration in cortical actin dynamics resulting in adaptation to load.
MT1-MMP:
+cartilage canals
Endoglin:
+Smad 1/5P
-Smad 2P
Smad2/3P(ALK5):
+Type II Collagen
Smad 1/5/8P(ALK1):
+Type X Collagen
+MMP13
-Height
ESL1:
+Height
-TGFBeta1
Cnidium:
+bFGF
+BMP-2
+IGF-1
RA:
+F-Spondin
Beta-Catenin:
-Chondrogenesis
-Sox9
F-Spondin:
-Height
+MMP-13
+ALP
Extracellular P(i):
+ALP
+RUNX2
+MMP-13
Smurf1:
-BMPs
-Height
Smad6:
-Height
-Smad1/5/8P
-BMPs
Smad7:
-TGF-Beta1
-BMP2
PTHrP:
+Sox9
+chondrocyte hypertrophy
IHH:
+chondrocyte proliferation
-Nkx3.2
FGFR1:
-Chondrogenesis
FGFR3:
+STAT1
-Height
-Ihh
STAT1:
-CCND1
CCND1:
-Runx2
FGF18:
-chondrocyte proliferation
Dynamic Compression(60min):
+COL2A1
MAPK(in chondrocytes):
+accelerates endochondral ossification
Microgravity:
+Sox9
+Aggrecan
+Type II Collagen
Ecdysterone:
+chondrogenesis
Twist1:
-Sox9
NfKappaB:
-Sox9
Runx2:
-Sox9
PTHrP:
+NLK3.2
Nkx3.2:
+Sox9
+Col2A1
Silicon:
+ALP
-Height
TSP3:
+Height
TSP5:
+Height
Col9:
+Height
Insulin:
-IGF1R
-IR
PGE2:
+IL6
+Type II Collagen
+MMP13
-Type X Collagen
-BMPs
Ascorbic Acid:
+ERK
+helps synthesize collagen matrix
Hydrostatic Pressure:
+Mitotic cell rounding into chondrogenesis
CNP:
+Height
+cGMP
CCN2:
+/- Height
Estrogen:
+/- Height
Proepithelin:
-NFKappaB
+Height
Harpogoside:
-MMP1
-MMP3
-MMP13
-NFKappaB
Acteoside:
-NFKappaB
Monday, May 28, 2012
Wednesday, May 23, 2012
Grow taller by inhibiting CHOP?
Unfortunately, it seems that Hiroki Yokota is focusing more on Salubrinal than LSJL. Salubrinal may have height increase applications and Salubrinal and Joint Loading have contrasting effects on EIF2alpha phosphorylation. EIF2alpha phosphorylation is bad for height growth as it decreases protein synthesis.
Salubrinal also has effects on upregulating mRNA including CHOP. Can CHOP help us grow taller?
Expression of CCAAT/enhancer-binding protein-beta (C/EBPbeta) and CHOP in the murine growth plate. Two possible key modulators of chondrocyte differentiation.
Akt-1 mediates survival of chondrocytes from endoplasmic reticulum-induced stress.
"Disruption of ER function interferes with protein folding and leads to the accumulation of unfolded proteins and the activation of an evolutionarily conserved adaptive response known as the unfolded protein response (UPR). If the UPR fails to counter the ER stress, caspase-mediated cell death ensues."
"Disruption of normal ER function is associated with dysfunction of the epiphyseal growth plate. In hypertrophic chondrocytes of transgenic mice expressing mutant collagen X, there is an accumulation of misfolded α1(X) chains and development of an UPR response"
"thapsigargin (inhibitor of sarcoplasmic and endoplasmic reticulum Ca2+ ATPases) causes a rapid initial release of Ca2+ from immature chondrocytes which returns to baseline levels after approximately 1 min."
"thapsigargin promotes a rapid phosphorylation of ERK that is sustained for 18 h."
Salubrinal also has effects on upregulating mRNA including CHOP. Can CHOP help us grow taller?
Expression of CCAAT/enhancer-binding protein-beta (C/EBPbeta) and CHOP in the murine growth plate. Two possible key modulators of chondrocyte differentiation.
"CCAAT/enhancer-binding protein-beta (C/EBPbeta) and C/EBP-homologous protein (CHOP) [is expressed] in the growth plate. Proximal tibial epiphyseal growth plates from ten 15-day-old Wistar rats were used. Anti-proliferating cell nuclear antigen (PCNA), anti-5-bromo-2'-deoxyuridine (BrdU) immunostaining, terminal transferase dUTP nick end-labelling (TUNEL) and nucleolar organiser region-associated proteins (AgNOR) techniques were peformed. The normal growth plate showed that C/EBPbeta and CHOP factors are expressed both in the germinative/ upper proliferative and in the lower proliferative zones. BdrU+ and PCNA+ cells were present exclusively in the germinative and proliferative zones, while TUNEL+ and AgNOR+ cells were seen in all three zones of the growth plate. Acellular areas, hypocellularity, the increase in cell death and anomalies in the architecture of the cell columns were observed in the growth plates of C/EBPbeta (-/-) knockout mice. C/EBPbeta and CHOP transcription factors may be key modulators participating in the chondrocyte differentiation process in the growth plate."
"CHOP is a member of the C/EBP family, acting as a dominant-negative inhibitor of DNA binding."
"The growth plate of C/EBPβ(-/-) mice showed a decrease in the number of chondrocytes, disarray in chondrocyte columns, global hypocellularity and interspersed acellular areas"
"Without transcription factor Sox-9, cells committed to chondrocyte lineage [may be] unable to form pre-cartilaginous condensations and to activate a number of cartilage markers, including Col2a1 and aggrecan"<-so maybe you need to activate Sox9 for LSJL to work properly.
"CHOP is involved in programmed cell death and the induction of CHOP was evident in C/EBPβ(-/-) mice. CHOP contributes to the IL-1 growth-inhibitory signals through increasing production of IL-6, and IL-1 inhibits replication of cartilage cells and stimulates production of matrix metalloproteinases, among other actions"<-Thus maybe CHOP is bad for height growth and thus Salubrinal may be bad too.
"The unfolded protein response (UPR) is an evolutionary conserved adaptive mechanism that permits cells to react and adjust to conditions of endoplasmic reticulum (ER) stress. In addition to UPR, phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal regulated kinase (ERK) signaling pathways protect a variety of cells from ER stress. chondrocytes [are susceptible] to ER stress. Low concentration of thapsigargin (10 nM) reduced the viability of a chondrocyte cell line (N1511 cells) and that these cells were approximately 100 fold more susceptible to thapsigargin-induced stress than fibroblasts. In thapsigargin and tunicamycin-stressed chondrocytes induction of the proapoptotic transcription factor CHOP preceded that of the anti-apoptotic BiP by 12 h. Although both of these agents caused sustained Akt and ERK phosphorylation; inhibition of Akt phosphorylation sensitized chondrocytes to ER stress, while blocking ERK signaling by U0126 had no effect. Akt-1, but not Akt-2 or Akt-3, is predominantly expressed in N1511 chondrocytes. siRNA-mediated knockdown of Akt-1 sensitized chondrocytes to ER stress, which was associated with increased capsase-3 activity and decreased Bcl(XL) expression. Under condition of ER stress, multiple signaling processes regulate chondrocyte's survival-death decisions. Rapid upregulation of CHOP likely contributes to chondrocyte death, while Akt-1-mediated inactivation of caspase 3 and induction of BclXL promotes survival."
"Disruption of ER function interferes with protein folding and leads to the accumulation of unfolded proteins and the activation of an evolutionarily conserved adaptive response known as the unfolded protein response (UPR). If the UPR fails to counter the ER stress, caspase-mediated cell death ensues."
"Disruption of normal ER function is associated with dysfunction of the epiphyseal growth plate. In hypertrophic chondrocytes of transgenic mice expressing mutant collagen X, there is an accumulation of misfolded α1(X) chains and development of an UPR response"
"thapsigargin (inhibitor of sarcoplasmic and endoplasmic reticulum Ca2+ ATPases) causes a rapid initial release of Ca2+ from immature chondrocytes which returns to baseline levels after approximately 1 min."
"thapsigargin promotes a rapid phosphorylation of ERK that is sustained for 18 h."
Thus, Salubrinal may actually reduce height by increasing chondrocyte death. LSJL does not upregulate CHOP in contrast to Salubrinal. So Zhang and Yokota need to table Salubrinal research and go back to LSJL so we can all grow taller.
According to Knee Loading Stimulates Bone Formation in Tail-Suspended Mouse Hindlimb, LSJL increases Akt phosphorylation. Loads were 1N at 5Hz for 5min. Sample was taken one hour after loading, 5 days after initiation. Twice as much load as was used compared to the gene expression study. Although LSJL increases ERK1/2-phosphorylation which can cause apoptosis Akt-p spares cells from apoptosis. Which may be why ERK1/2-p sometimes is pro-chondrogenic and sometimes not. ERK1/2-p is both pro-chondrogenic genes and pro-apoptosis so Akt-p reduces the apoptosis resulting in a net chondrogenic effect
CHOP doesn't always cause apoptosis:
Transcriptional profiling of chondrodysplasia growth plate cartilage reveals adaptive ER-stress networks that allow survival but disrupt hypertrophy.
According to Knee Loading Stimulates Bone Formation in Tail-Suspended Mouse Hindlimb, LSJL increases Akt phosphorylation. Loads were 1N at 5Hz for 5min. Sample was taken one hour after loading, 5 days after initiation. Twice as much load as was used compared to the gene expression study. Although LSJL increases ERK1/2-phosphorylation which can cause apoptosis Akt-p spares cells from apoptosis. Which may be why ERK1/2-p sometimes is pro-chondrogenic and sometimes not. ERK1/2-p is both pro-chondrogenic genes and pro-apoptosis so Akt-p reduces the apoptosis resulting in a net chondrogenic effect
CHOP doesn't always cause apoptosis:
Transcriptional profiling of chondrodysplasia growth plate cartilage reveals adaptive ER-stress networks that allow survival but disrupt hypertrophy.
"Metaphyseal chondrodysplasia, Schmid type (MCDS) is characterized by mild short stature and growth plate hypertrophic zone expansion, and caused by collagen X mutations. ER stress [is important] in the pathology of MCDS by recapitulating the disease phenotype by expressing misfolding forms of collagen X (Schmid) or thyroglobulin (Cog) in the hypertrophic zone. Here we characterize the Schmid and Cog ER stress signaling networks by transcriptional profiling of microdissected mutant and wildtype hypertrophic zones. Both models displayed similar unfolded protein responses (UPRs), involving activation of canonical ER stress sensors and upregulation of their downstream targets, including molecular chaperones, foldases, and ER-associated degradation machinery. Also upregulated were the emerging UPR regulators Wfs1 and Syvn1, recently identified UPR components including Armet and Creld2, and genes not previously implicated in ER stress such as Steap1{up in LSJL} and Fgf21. Despite upregulation of the Chop/Cebpb pathway, apoptosis was not increased in mutant hypertrophic zones. ER stress and disrupted chondrocyte maturation [were present] throughout mutant [growth plate] hypertrophic zones. This disruption was defined by profiling the expression of wild type growth plate zone gene signatures in the mutant hypertrophic zones. Hypertrophic zone gene upregulation and proliferative zone gene downregulation were both inhibited in Schmid hypertrophic zones, resulting in the persistence of a proliferative chondrocyte-like expression profile in ER-stressed Schmid chondrocytes."
"Activated Perk undergoes dimerization and trans-autophosphorylation, and is then able to phosphorylate the eukaryotic translation initiation factor 2-alpha (Eif2α), preventing formation of the translational initiation complex"
The unfolded protein response does affect hypertrophic chondrocytes:
Hypertrophic chondrocytes have a limited capacity to cope with increases in endoplasmic reticulum stress without triggering the unfolded protein response.
"Mutations causing metaphyseal chondrodysplasia type Schmid (MCDS) (e.g., Col10a1p.N617K) induce the pathology by a mechanism involving increased endoplasmic reticulum (ER) stress triggering an unfolded protein response (UPR) in hypertrophic chondrocytes. Here we correlate the expression of mutant protein with the onset of the UPR and disease pathology (hypertrophic zone [HZ] expansion) in MCDS and ColXTg(cog) mouse lines from E14.5 to E17.5. Embryos homozygous for the Col10a1p.N617K mutation displayed a delayed secretion of mutant collagen X accompanied by a UPR at E14.5, delayed ossification of the primary center at E15.5, and an expanded HZ at E17.5. Heterozygote embryos expressed mutant collagen X from E14.5 but exhibited no evidence of a UPR or an HZ expansion until after E17.5. Embryos positive for the ER stress-inducing ColXTg(cog) allele expressed Tg(cog) at E14.5, but the onset of the UPR was not apparent until E15.5 in homozygous and E17.5 in hemizygous embryos. Only homozygous embryos exhibited an HZ expansion at E17.5. The differential onset of the UPR and pathology, dependent on mutation type and gene dosage, indicates that hypertrophic chondrocytes have a latent capacity to deal with ER stress, which must be exceeded to trigger the UPR and HZ expansion."
The mutant mice experienced delayed recruitment of osteoclasts.
"the hypertrophic chondrocytes expressing mutant forms of collagen X experienced a profound UPR, a disrupted differentiation pattern including decreased expression of VEGF, and a decreased recruitment of osteoclasts to the VIF, causing an expansion of the hypertrophic zone."
The unfolded protein response does affect hypertrophic chondrocytes:
Hypertrophic chondrocytes have a limited capacity to cope with increases in endoplasmic reticulum stress without triggering the unfolded protein response.
"Mutations causing metaphyseal chondrodysplasia type Schmid (MCDS) (e.g., Col10a1p.N617K) induce the pathology by a mechanism involving increased endoplasmic reticulum (ER) stress triggering an unfolded protein response (UPR) in hypertrophic chondrocytes. Here we correlate the expression of mutant protein with the onset of the UPR and disease pathology (hypertrophic zone [HZ] expansion) in MCDS and ColXTg(cog) mouse lines from E14.5 to E17.5. Embryos homozygous for the Col10a1p.N617K mutation displayed a delayed secretion of mutant collagen X accompanied by a UPR at E14.5, delayed ossification of the primary center at E15.5, and an expanded HZ at E17.5. Heterozygote embryos expressed mutant collagen X from E14.5 but exhibited no evidence of a UPR or an HZ expansion until after E17.5. Embryos positive for the ER stress-inducing ColXTg(cog) allele expressed Tg(cog) at E14.5, but the onset of the UPR was not apparent until E15.5 in homozygous and E17.5 in hemizygous embryos. Only homozygous embryos exhibited an HZ expansion at E17.5. The differential onset of the UPR and pathology, dependent on mutation type and gene dosage, indicates that hypertrophic chondrocytes have a latent capacity to deal with ER stress, which must be exceeded to trigger the UPR and HZ expansion."
The mutant mice experienced delayed recruitment of osteoclasts.
"the hypertrophic chondrocytes expressing mutant forms of collagen X experienced a profound UPR, a disrupted differentiation pattern including decreased expression of VEGF, and a decreased recruitment of osteoclasts to the VIF, causing an expansion of the hypertrophic zone."
Monday, May 21, 2012
Grow taller by removing Lead(Pb) from your diet?
Hair lead levels to evaluate the subclinical impact of lead on growth in Sardinian children (Italy).
"Three samples [were] collected at different times: 1998, 2002, 2007. The total sample consisted of 825 children between 11 and 14 years of age living in different municipalities of Sardinia (Italy). [We measured] the lead concentration in hair (PbH).
The mean PbH is much higher in 1998 (5.84 μg/g) than in 2002 (1.49 μg/g) and 2007 (0.78 μg/g). [There is an] impact of lead on growth that differs according to the mean lead concentration in the hair. For 1998, the relationships between all three anthropometric variables[height, sitting height, and estimate leg length] and logPbH are significantly negative. For 2002, there are significant negative associations between height and estimated leg length and logPbH but not between sitting height and logPbH. For 2007, there are not significant associations between logPbH and anthropometric variables."
Why would the effects of lead change over the years?
"Lead is widespread in the environment, with several anthropogenic sources such as traffic, lead battery production, lead-containing plastics and paint, solder, ceramic table and kitchen ware, combustion of fossil fuels, metallurgy, smelting processes, [and] direct ingestion of dust"
According to the study, the mean amount of lead in hair also lowered greatly throughout the years. So maybe lead only has negative impacts at very high quantities?
1998 Mean Lead 7.40 Decrease Height(More lead in hair correlates with height decrease)
2002 Mean Lead 1.17 Decrease Height
2007 Mean Lead 0.76 Increase Height(more lead in hair correlates with height increase)
So likely lead has an equilibrium level to maximize height. Of course the study had other issues as lead levels in the hair are not a perfect correlate to lead levels in serum.
They found a positive relationship between upper arm muscle area and height. This could be myostatin related.
"The negative effects of lead on growth are due to the fact that this heavy metal, a calcium antagonist, has a high affinity for bone tissue; many of the circulating ions are deposited in bone, inhibiting development of the long bones and flat bones via activation of chondrocytic inflammation which slows or inhibits cell division. The stunting effect of blood lead on linear growth indicates a dose-related reduction in stature by about 1 to 3 cm for each 10 μg/dL increase in blood lead level."
"[The] greater influence of lead on chondrocyte proliferation, hypertrophy, and matrix calcification at long bone growth plates is a leading cause of reduced growth in leg and arm lengths, while a secondary cause of reduced height is probably reduced osteoblast activity and bone remodeling. Growth plates of the lower extremities, and to a lesser extent of the upper extremities, [may be] more susceptible to lead levels because they grow more rapidly early in life when children are prone to having higher blood lead levels"
The 2007 group had the shortest mean height. The 2002 group had the highest mean height. The 2002 group were likely closest to the equilibrium value of lead.
Thus obtaining an equilibrium quantity of lead may increase height.
Lead induces chondrogenesis and alters transforming growth factor-beta and bone morphogenetic protein signaling in mesenchymal cell populations.
"Skeletal growth is stunted in lead-exposed children.
Pb [influences] chondrogenesis in murine limb bud mesenchymal cells (MSCs). The effects of Pb on transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP) signaling was studied. [We studied] cyclic adenosine monophosphate response element binding protein (CREB), beta-catenin, AP-1, and nuclear factor-kappa B (NF-kappaB) signaling. We also used an ectopic bone formation assay to determine how Pb affects chondrogenesis in vivo.
Pb-exposed MSCs showed enhanced basal and TGF-beta/BMP induction of chondrogenesis, evidenced by enhanced nodule formation and up-regulation of Sox-9, type 2 collagen, and aggrecan, all key markers of chondrogenesis. Chondrogenesis [was enhanced] during ectopic bone formation in mice preexposed to Pb via drinking water. In MSCs, Pb enhanced TGF-beta but inhibited BMP-2 signaling as measured by analyses of Smad phosphorylation. Although Pb had no effect on basal CREB or Wnt/beta-catenin pathway activity, it induced NFkappaB signaling and inhibited AP-1 signaling.{all things that affect chondrogenesis}
The in vitro and in vivo induction of chondrogenesis by Pb [may involve the signaling pathways] TGF-beta, BMP, AP-1, and NFkappaB."
"Prostaglandin E2, through protein kinase A signaling also induces chondrogenesis, whereas retinoic acid is considered an inhibitor of chondrogenic commitment possibly via down-regulation of TGF-β/Smad signaling"
Pb may also "[induce] ERK1/2 (extracellular signal regulated kinase 1 and 2) and p38 (mitogen-activated protein kinase; MAPK) phosphorylation"
"Although the effect of BMP-2 was slightly greater (3.2-fold) than that of TGF-β (1.7-fold), the induction of chondrogenesis by both growth factors was enhanced by Pb. In the presence of 10 μM Pb, BMP-2 induced chondrogenesis 5-fold and TGF-β induced a 3-fold increase"
"Pb dose-dependently enhanced the expression of these genes, with 10-μM Pb inducing a 2-fold increase in Sox9, a 5-fold increase in col2, and a 2.5-fold increase in aggrecan compared with untreated cultures"<-doses above 10 were not tried so we can't see the equilibrium point.
"Pb affects neither basal BMP-2 nor TGF-β signaling; thus it is unlikely that the effect of Pb on chondrogenesis is related to a direct alteration of these signaling pathways. Moreover, although Pb enhanced the effect of BMP-2 on chondrogenesis, it acted as an inhibitor of Smad1/5/8 signaling."
"although neither Pb nor TGF-β alone affected the expression of BMP-6, in combination they induced its expression 3-fold"
"signaling on the NFκB pathway has been shown to destabilize Sox9 mRNA and inhibit chondrogenesis"
Lead induces an osteoarthritis-like phenotype in articular chondrocytes through disruption of TGF-β signaling.
Lead induces chondrogenesis and alters transforming growth factor-beta and bone morphogenetic protein signaling in mesenchymal cell populations.
"Skeletal growth is stunted in lead-exposed children.
Pb [influences] chondrogenesis in murine limb bud mesenchymal cells (MSCs). The effects of Pb on transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP) signaling was studied. [We studied] cyclic adenosine monophosphate response element binding protein (CREB), beta-catenin, AP-1, and nuclear factor-kappa B (NF-kappaB) signaling. We also used an ectopic bone formation assay to determine how Pb affects chondrogenesis in vivo.
Pb-exposed MSCs showed enhanced basal and TGF-beta/BMP induction of chondrogenesis, evidenced by enhanced nodule formation and up-regulation of Sox-9, type 2 collagen, and aggrecan, all key markers of chondrogenesis. Chondrogenesis [was enhanced] during ectopic bone formation in mice preexposed to Pb via drinking water. In MSCs, Pb enhanced TGF-beta but inhibited BMP-2 signaling as measured by analyses of Smad phosphorylation. Although Pb had no effect on basal CREB or Wnt/beta-catenin pathway activity, it induced NFkappaB signaling and inhibited AP-1 signaling.{all things that affect chondrogenesis}
The in vitro and in vivo induction of chondrogenesis by Pb [may involve the signaling pathways] TGF-beta, BMP, AP-1, and NFkappaB."
"Prostaglandin E2, through protein kinase A signaling also induces chondrogenesis, whereas retinoic acid is considered an inhibitor of chondrogenic commitment possibly via down-regulation of TGF-β/Smad signaling"
Pb may also "[induce] ERK1/2 (extracellular signal regulated kinase 1 and 2) and p38 (mitogen-activated protein kinase; MAPK) phosphorylation"
"Although the effect of BMP-2 was slightly greater (3.2-fold) than that of TGF-β (1.7-fold), the induction of chondrogenesis by both growth factors was enhanced by Pb. In the presence of 10 μM Pb, BMP-2 induced chondrogenesis 5-fold and TGF-β induced a 3-fold increase"
"Pb dose-dependently enhanced the expression of these genes, with 10-μM Pb inducing a 2-fold increase in Sox9, a 5-fold increase in col2, and a 2.5-fold increase in aggrecan compared with untreated cultures"<-doses above 10 were not tried so we can't see the equilibrium point.
"Pb affects neither basal BMP-2 nor TGF-β signaling; thus it is unlikely that the effect of Pb on chondrogenesis is related to a direct alteration of these signaling pathways. Moreover, although Pb enhanced the effect of BMP-2 on chondrogenesis, it acted as an inhibitor of Smad1/5/8 signaling."
"although neither Pb nor TGF-β alone affected the expression of BMP-6, in combination they induced its expression 3-fold"
"signaling on the NFκB pathway has been shown to destabilize Sox9 mRNA and inhibit chondrogenesis"
Lead induces an osteoarthritis-like phenotype in articular chondrocytes through disruption of TGF-β signaling.
"As lead is concentrated in articular cartilage, we hypothesize that it can disrupt normal chondrocyte phenotype through suppression of TGF-β signaling. [We] examine the effects of lead exposure in vivo and in vitro at biologically relevant levels, from 1 nM to 10 µM on viability, collagen levels, matrix degrading enzyme activity, TGF-β signaling, and articular surface morphology. [Chondrocyte] viability was unchanged at levels ≤100 µM Pb, but low and high level lead in vivo exposure resulted in fibrillation and degeneration of the articular surface. Lead treatment also decreased levels of type II collagen and increased type X collagen, in vivo and in vitro. MMP13 activity increased in a dose-dependent manner. Active caspase 3 and 8 were dose-dependently elevated, and treatment with 10 µM Pb resulted in increases of 30% and 500%, respectively. Increasing lead treatment resulted in a corresponding reduction in TGF-β reporter activity, with a 95% reduction at 10µM. Levels of phosphoSmad2 and 3 were suppressed in vitro and in vivo and lead dose-dependently increased Smurf2."
Smurf2 degrades Smad2/3.
Developmental exposure to As, Cd and Pb-mixture diminishes skeletal growth and causes osteopenia at maturity via osteoblast and chondrocyte malfunctioning in female rats.
"We studied the effect of metal mixture (MM), comprising of As[Arsenic], Cd[Cadmium] and Pb[Lead], in developing female rat skeleton from gestation day-5 until postnatal day-60 (P-60). MM resulted in synergistic inhibition in viability and differentiation of osteoblasts in vitro, likely induced by reactive oxygen species. MM, administered at their most frequently occurring concentrations present in the ground-water of India, i.e. As: 0.38ppm, Pb: 0.22 ppm and Cd: 0.098 ppm {so enough concentrations to influence water are present in some drinking waters} or 10× of the ratio to developing rats exhibited a synergistic decrease in ex vivo mineralization of bone marrow stromal (osteoprogenitor) cells. MM group showed a dose-dependent attenuation in weight and axial lengths, and shortening of tibias at P-60. Furthermore, the growth plate was shortened, which was associated with shorter proliferative- and hypertrophic zones, decreased parathyroid hormone-related protein and Indian hedgehog expression in the chondrocytes, reduced primary- and secondary spongiosa, and hypomineralized osteoids - a major characteristic of osteomalacia. In addition, compared to the control, MM treated rats were clearly osteopenic based on BMD, micro-architecture, biomechanical strength, and particularly the biochemical profile, that suggested high turnover bone loss. Finally, in comparison to the control, the fracture healing ability of MM group was delayed and accompanied by inferior quality of the healed bone."
Lead contamination has been found in drinking water in the United States.
"During development, skeletal tissue assimilates heavy metals to which they are exposed. The incorporated metals are eliminated by resorption" Several years are required to eliminate these metals.
The reduction in tibial lengths by the Metal Mixture was dose dependent.
Developmental exposure to As, Cd and Pb-mixture diminishes skeletal growth and causes osteopenia at maturity via osteoblast and chondrocyte malfunctioning in female rats.
"We studied the effect of metal mixture (MM), comprising of As[Arsenic], Cd[Cadmium] and Pb[Lead], in developing female rat skeleton from gestation day-5 until postnatal day-60 (P-60). MM resulted in synergistic inhibition in viability and differentiation of osteoblasts in vitro, likely induced by reactive oxygen species. MM, administered at their most frequently occurring concentrations present in the ground-water of India, i.e. As: 0.38ppm, Pb: 0.22 ppm and Cd: 0.098 ppm {so enough concentrations to influence water are present in some drinking waters} or 10× of the ratio to developing rats exhibited a synergistic decrease in ex vivo mineralization of bone marrow stromal (osteoprogenitor) cells. MM group showed a dose-dependent attenuation in weight and axial lengths, and shortening of tibias at P-60. Furthermore, the growth plate was shortened, which was associated with shorter proliferative- and hypertrophic zones, decreased parathyroid hormone-related protein and Indian hedgehog expression in the chondrocytes, reduced primary- and secondary spongiosa, and hypomineralized osteoids - a major characteristic of osteomalacia. In addition, compared to the control, MM treated rats were clearly osteopenic based on BMD, micro-architecture, biomechanical strength, and particularly the biochemical profile, that suggested high turnover bone loss. Finally, in comparison to the control, the fracture healing ability of MM group was delayed and accompanied by inferior quality of the healed bone."
Lead contamination has been found in drinking water in the United States.
"During development, skeletal tissue assimilates heavy metals to which they are exposed. The incorporated metals are eliminated by resorption" Several years are required to eliminate these metals.
The reduction in tibial lengths by the Metal Mixture was dose dependent.
Robert Ballock and Cory Xian: Potential Height Increase Allies
Robert Ballock and Cory Xian are both studying growth plate regeneration.
I found this grant.
GROWTH PLATE REGENERATION
"Co-cultured chondrocytes and osteoblasts implanted into tibial bone defects in vivo [may] recapitulate the function of the normal growth plate and result in the reformation of columnar physeal architecture and resumption of longitudinal growth[our goal is to stimulate chondrogenesis with LSJL in the bone already]. [We will] determine the degree to which this optimized physeal construct replicates the function of the normal growth plate in vivo following implantation into a complete growth plate defect. Successful regeneration of growth plate cartilage architecture in vivo would have a transformational impact on the practice of pediatric orthopaedic surgery, providing not only the ability to replace growth plates irreversibly damaged by trauma, infection or irradiation, but also the possibility of restoring longitudinal growth in individuals beyond the age of skeletal maturity."
"key observations [include] the discovery that terminal differentiation of growth plate chondrocytes was a default pathway that could be accelerated by thyroid hormone, and that morphogenesis of columnar cartilage in the growth plate could be recapitulated in our serum-free three-dimensional pellet cultures by addition of thyroid hormone."<-so we have to explore thyroid hormone as a means of enhancing height growth more.
I found this grant.
GROWTH PLATE REGENERATION
"Co-cultured chondrocytes and osteoblasts implanted into tibial bone defects in vivo [may] recapitulate the function of the normal growth plate and result in the reformation of columnar physeal architecture and resumption of longitudinal growth[our goal is to stimulate chondrogenesis with LSJL in the bone already]. [We will] determine the degree to which this optimized physeal construct replicates the function of the normal growth plate in vivo following implantation into a complete growth plate defect. Successful regeneration of growth plate cartilage architecture in vivo would have a transformational impact on the practice of pediatric orthopaedic surgery, providing not only the ability to replace growth plates irreversibly damaged by trauma, infection or irradiation, but also the possibility of restoring longitudinal growth in individuals beyond the age of skeletal maturity."
So this guy wants to help people grow taller. Here's his profile. Here's the highlights:
"We initially determined that the principal site of thyroid hormone action during skeletal maturation was regulation of the critical transition between cell proliferation and terminal hypertrophic differentiation in the growth plate.In addition to characterizing the expression of thyroid hormone receptors in this tissue, we also explored the interactions between thyroid hormone, vitamin D, and retinoic acid in regulating terminal differentiation of growth plate chondrocytes. Other work established an important link between thyroid hormone-induced terminal differentiation and upregulation of cell cycle proteins p21cip-1, waf-1 and p57 kip-1, indicating that growth arrest at the G1-S restriction point of the cell cycle is an obligatory step in the terminal differentiation process of growth plate chondrocytes."
"These studies have demonstrated that peroxisome proliferator activated receptors (PPARs), which are upregulated in response to a high fat diet, are also expressed in growth plate chondrocytes and interfere with the normal transcriptional activation function of thyroid hormone receptors in these cells, eventually resulting in the inhibition of terminal differentiation and matrix mineralization that allows the subsequent mechanical failure of the growth plate to occur."<-This guy knows all the studies that have been highlighted on this blog.
He has $157,000 funding. We should find out what he thinks about LSJL & growth plate regeneration.
Here's a Ballock study that seems related to the grant:
Leptin Antagonizes Peroxisome Proliferator-Activated Receptor-γ Signaling in Growth Plate Chondrocytes.
Here's a Ballock study that seems related to the grant:
Leptin Antagonizes Peroxisome Proliferator-Activated Receptor-γ Signaling in Growth Plate Chondrocytes.
"Leptin is an obesity-associated cytokine-like hormone encoded by the ob gene. Leptin promotes proliferation and differentiation of chondrocytes, suggesting a peripheral role of leptin in regulating growth plate function. Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcriptional regulator of adipogenesis. Locally, PPARγ negatively regulates chondrogenic differentiation and terminal differentiation in the growth plate. Leptin may suppress the inhibitory effects of PPARγ on growth plate chondrocytes. Chondrocytes were collected from distal femoral growth plates of newborn rats and were cultured in monolayer or cell pellets in the presence or absence of leptin and the PPARγ agonist ciglitazone. The results show that leptin attenuates the suppressive effects of PPARγ on chondrogenic differentiation and T3-mediated chondrocyte hypertrophy. Leptin treatment also leads to a mild downregulation of PPAR mRNA expression and a significant MAPK/ERK-dependent PPARγ phosphorylation at serine 112/82. Blocking MAPK/ERK function with PD98059 confirmed that leptin antagonizes PPARγ function in growth plate chondrocytes through the MAPK/ERK signaling pathway. leptin signaling in growth plate cells is also negatively modulated by activation of PPARγ, implying that these two signaling pathways are mutually regulated in growth plate chondrocytes."
"Binding of leptin to its receptor triggers activation of janus kinases (JAKs), leading to phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3)"
"Suppressor of cytokine signaling 3 (SOCS3){upregulated by LSJL} protein acts as a feedback inhibitor of the JAK/STAT3 pathway, inhibiting STAT3 phosphorylation"
"results in disturbed columnar structure, decreased type X collagen expression{up in LSJL}, increased apoptosis, and premature mineralization in the growth plates"
"leptin synergizes with thyroid hormone in modulating terminal differentiation of growth plate chondrocytes"
"PPARgamma is expressed in growth plate chondrocytes, and activation of PPARgamma promotes adipogenic transdifferentiation of growth plate chondrocytes, while attenuating[represses] both chondrogenic differentiation and terminal differentiation "
"Incubating the growth plate chondrocytes with the PPARgamma agonist[activator] ciglitazone for 5 days decreased both Col2a1 and aggrecan mRNA expression"
"Coaddition of leptin reduced the ciglitazone-induced inhibition of these chondrogenic differentiation markers." Leptin inhibited the PPARg increase in PPRE.
"leptin-induced increases in phosphorylated PPARg were blocked by coincubation with the MAPK/ERK inhibitor PD98059, but not by the JNK inhibitor SP600125"
"Both MAPK/ERK and MAPK/JNK signaling can phosphorylate PPARg at a consensus MAPK phosphorylation site"
"leptin has been reported to increase phosphorylation of ERK1/2 in a time- and dose-dependent manner, but not phosphorylation of JNK"
And another study listed as being directly related to the grant:
Biodegradable photo-crosslinked alginate nanofibre scaffolds with tuneable physical properties, cell adhesivity and growth factor release.
Here's what another study had to say about growth plate regeneration(his email address: cory.xian@unisa.edu.au <-Search for papers by Xian CJ):
POTENTIALS AND CHALLENGES OF GROWTH PLATE REGENERATION USING EX VIVO EXPANDED MESENCHYMAL STEM CELLS OR MOBOLISING ENDOGENOUS PROGENITOR CELLS
We are trying to mobilize endogenous progenitor cells with LSJL.
"Recent studies using rabbit models to investigate the efficacy of bone marrow mesenchymal stem cells (MSC) to promote cartilage regeneration and prevent bone defects following growth plate injury have shown promise. However, translational studies in large animal models (such as lambs), which more closely resemble the human condition, are lacking.
Very recently, our labs have shown that ovine bone marrow MSC are multipotential and can form cartilage-like tissue when transplanted into mice. However, using a growth plate injury model in lambs, analogous to those described in the rabbit, autologous marrow MSC seeded into gelatine scaffold containing chondrogenic factor TGF-1{Maybe TGF-1 wasn't enough}, failed to promote growth plate regeneration. To date, no large animal studies have reported successful regeneration of injured growth plate cartilage using MSC highlighting the possibility that ex vivo expanded MSC may not represent a viable cellular therapy for growth plate injury repair. In addition, using a growth plate injury repair model in young rats, our studies have also focused on understanding mechanisms of the faulty repair and identifying potential targets for enhancing growth plate regeneration using endogenous progenitor cells. We have observed that bony repair of injured growth plate is preceded sequentially by inflammatory, fibrogenic, chondrogenic and osteogenic responses involving both intramembranous and endochondral ossification mechanisms. We have observed infiltration of mesenchymal progenitor cells into the injury site, some of which have the potential to differentiate to osteoblasts or chondrocytes and contribute to the bony repair of the injured growth plate.
This presentation will focus on our studies examining the efficacy of ex vivo expanded autologous MSC to enhance growth plate regeneration in the ovine model and work using a rat model aimed at identifying potential targets for enhancing cartilage regeneration by mobilising endogenous stromal progenitor cells."
Preclinical studies on mesenchymal stem cell-based therapy for growth plate cartilage injury repair.
And another study listed as being directly related to the grant:
Biodegradable photo-crosslinked alginate nanofibre scaffolds with tuneable physical properties, cell adhesivity and growth factor release.
"Nanofibrous scaffolds are of interest in tissue engineering due to their high surface area to volume ratio, interconnected pores, and architectural similarity to the native extracellular matrix. Our laboratory recently developed a biodegradable, photo-crosslinkable alginate biopolymer. The material [can] be electrospun into a nanofibrous matrix, and [can] enhance cell adhesion and proliferation on these matrices by covalent modification with cell adhesion peptides. Additionally, the potential of covalently incorporating heparin into the hydrogels during the photopolymerisation process to sustain the release of a heparin binding growth factor via affinity interactions was demonstrated. Electrospun photo-crosslinkable alginate nanofibrous scaffolds endowed with cell adhesion ligands and controlled delivery of growth factors may allow for improved regulation of cell behaviour for regenerative medicine."
"by covalently modifying the alginate with heparin, FGF-2 was released in a sustained manner over the course of one week from these scaffolds, and the released growth factor retained its bioactivity as demonstrated by enhanced proliferation of HDFs[human dermal fibroblasts]"
Here's what another study had to say about growth plate regeneration(his email address: cory.xian@unisa.edu.au <-Search for papers by Xian CJ):
POTENTIALS AND CHALLENGES OF GROWTH PLATE REGENERATION USING EX VIVO EXPANDED MESENCHYMAL STEM CELLS OR MOBOLISING ENDOGENOUS PROGENITOR CELLS
We are trying to mobilize endogenous progenitor cells with LSJL.
"Recent studies using rabbit models to investigate the efficacy of bone marrow mesenchymal stem cells (MSC) to promote cartilage regeneration and prevent bone defects following growth plate injury have shown promise. However, translational studies in large animal models (such as lambs), which more closely resemble the human condition, are lacking.
Very recently, our labs have shown that ovine bone marrow MSC are multipotential and can form cartilage-like tissue when transplanted into mice. However, using a growth plate injury model in lambs, analogous to those described in the rabbit, autologous marrow MSC seeded into gelatine scaffold containing chondrogenic factor TGF-1{Maybe TGF-1 wasn't enough}, failed to promote growth plate regeneration. To date, no large animal studies have reported successful regeneration of injured growth plate cartilage using MSC highlighting the possibility that ex vivo expanded MSC may not represent a viable cellular therapy for growth plate injury repair. In addition, using a growth plate injury repair model in young rats, our studies have also focused on understanding mechanisms of the faulty repair and identifying potential targets for enhancing growth plate regeneration using endogenous progenitor cells. We have observed that bony repair of injured growth plate is preceded sequentially by inflammatory, fibrogenic, chondrogenic and osteogenic responses involving both intramembranous and endochondral ossification mechanisms. We have observed infiltration of mesenchymal progenitor cells into the injury site, some of which have the potential to differentiate to osteoblasts or chondrocytes and contribute to the bony repair of the injured growth plate.
This presentation will focus on our studies examining the efficacy of ex vivo expanded autologous MSC to enhance growth plate regeneration in the ovine model and work using a rat model aimed at identifying potential targets for enhancing cartilage regeneration by mobilising endogenous stromal progenitor cells."
Preclinical studies on mesenchymal stem cell-based therapy for growth plate cartilage injury repair.
"MSCs express adhesion molecules and can migrate to sites of injury healing" CXCR4 and MCP3 are two proteins involved in MSC homing.
"some success [was observed] when allogeneic chondrocytes (collected from the growth plate) were delivered into the growth plate injury site of White New Zealand rabbits. chondrocytes filled the defect and were able to form columns. In addition, although there were signs of endochondral ossification at the base of the injury site, no rejection of the implanted chondrocytes occurred"
"stimuli or signal molecules controlling their migration, proliferation (PDGF-BB, FGF-2{up in LSJL}), and chondrogenic differentiation (TGF-β1, IGF-I)."
"only a certain amount of gene expression was needed to induce chondrogenic differentiation of bone marrow-derived cells, and that overexpression by gene-induced transduction may have negative, opposing effect on chondrogenic differentiation"
"collagen family excluding collagen-V as well as adhesion proteins such as fibronection and vitronectin all influenced and encouraged the migratory and proliferatory behavior of MSCs"
"some success [was observed] when allogeneic chondrocytes (collected from the growth plate) were delivered into the growth plate injury site of White New Zealand rabbits. chondrocytes filled the defect and were able to form columns. In addition, although there were signs of endochondral ossification at the base of the injury site, no rejection of the implanted chondrocytes occurred"
"stimuli or signal molecules controlling their migration, proliferation (PDGF-BB, FGF-2{up in LSJL}), and chondrogenic differentiation (TGF-β1, IGF-I)."
"only a certain amount of gene expression was needed to induce chondrogenic differentiation of bone marrow-derived cells, and that overexpression by gene-induced transduction may have negative, opposing effect on chondrogenic differentiation"
"collagen family excluding collagen-V as well as adhesion proteins such as fibronection and vitronectin all influenced and encouraged the migratory and proliferatory behavior of MSCs"
Sunday, May 20, 2012
Joint distraction
Since joint distraction in places such as the jaw and maxilla may work so too may it work in other regions.
Atlantoaxial joint distraction for treatment of basilar invagination secondary to rheumatoid arthritis.
"oint distraction group significantly reduced the numbers of MMP13+ and type X collagen (COL X)-positive chondrocytes compared to the other two groups"<-this is actually not a good thing when inducing endochondral ossification
Atlantoaxial joint distraction for treatment of basilar invagination secondary to rheumatoid arthritis.
"We present our experience of treating two cases of rheumatoid arthritis involving the craniovertebral junction and having marked basilar invagination by an alternative treatment method. In both the cases, the facets were osteoporotic and were not suitable for screw implantation. The patients were 66 and 72 years of age and both patients were females. Both the patients presented with complaints of progressively increasing spastic quadriparesis. Surgery involved attempts to reduce the basilar invagination and restore the height of the 'collapsed' lateral mass by manual distraction of the facets of the atlas and axis and forced impaction of titanium spacers in the joint in addition to bone graft harvested from the iliac crest. The procedure also provided stabilization of the region. No other fixation procedure involving wires, screws, plate and rods was carried out simultaneously. Following surgery both the patients showed symptomatic improvement and partial restoration of craniovertebral alignments. Follow-up is of 2 and 24 months. Distraction of the facets of atlas and axis and impaction of metal implant and bone graft in the facet joint can assist in reduction of basilar invagination and fixation of the region in selected cases of rheumatoid arthritis involving the craniovertebral junction."
<-Nothing really here.
https://onlinelibrary.wiley.com/doi/full/10.1002/art.38906"Knee osteoarthritis (OA) is a degenerative joint disorder characterized by cartilage, bone, and synovial tissue changes that lead to pain and functional impairment. Joint distraction is a treatment that provides long-term improvement in pain and function accompanied by cartilage repair, as evaluated indirectly by imaging studies and measurement of biochemical markers. The purpose of this study was to evaluate cartilage tissue repair directly by histologic and biochemical assessments after joint distraction treatment.
In 27 dogs, OA was induced in the right knee joint (groove model; surgical damage to the femoral cartilage). After 10 weeks of OA development, the animals were randomized to 1 of 3 groups. Two groups were fitted with an external fixator, which they wore for a subsequent 10 weeks (one group with and one without joint distraction), and the third group had no external fixation (OA control group). Pain/function was studied by force plate analysis. Cartilage integrity and chondrocyte activity of the surgically untouched tibial plateaus were analyzed 25 weeks after removal of the fixator.
Changes in force plate analysis values between the different treatment groups were not conclusive. Features of OA were present in the OA control group, in contrast to the generally less severe damage after joint distraction. Those treated with joint distraction had lower macroscopic and histologic damage scores, higher proteoglycan content, better retention of newly formed proteoglycans, and less collagen damage. In the fixator group without distraction, similarly diminished joint damage was found, although it was less pronounced.
Joint distraction as a treatment of experimentally induced OA results in cartilage repair activity, which corroborates the structural observations of cartilage repair indicated by surrogate markers in humans."
In 27 dogs, OA was induced in the right knee joint (groove model; surgical damage to the femoral cartilage). After 10 weeks of OA development, the animals were randomized to 1 of 3 groups. Two groups were fitted with an external fixator, which they wore for a subsequent 10 weeks (one group with and one without joint distraction), and the third group had no external fixation (OA control group). Pain/function was studied by force plate analysis. Cartilage integrity and chondrocyte activity of the surgically untouched tibial plateaus were analyzed 25 weeks after removal of the fixator.
Changes in force plate analysis values between the different treatment groups were not conclusive. Features of OA were present in the OA control group, in contrast to the generally less severe damage after joint distraction. Those treated with joint distraction had lower macroscopic and histologic damage scores, higher proteoglycan content, better retention of newly formed proteoglycans, and less collagen damage. In the fixator group without distraction, similarly diminished joint damage was found, although it was less pronounced.
Joint distraction as a treatment of experimentally induced OA results in cartilage repair activity, which corroborates the structural observations of cartilage repair indicated by surrogate markers in humans."
"Knee joint distraction is a surgical procedure by which the two bony ends of a joint and, with those, the cartilage surfaces are gradually separated to a certain extent (∼5 mm) for a given period of time (6–8 weeks) by use of an external fixation frame. "
"The (transient) distraction results in a decrease in wear and tear of the cartilage surfaces. Furthermore, it results in intermittent fluid pressure changes during loading and unloading of the distracted joint (due to springs and flexibility in the distraction frame)"
Distraction does seem to make the cartilage more similar to that undergoing endochondral ossification.
"Joint distraction reduced the level of secondary inflammation, cartilage degeneration and subchondral bone aberrant change, joint distraction may be a strategy for slowing OA progression."
