beta-Catenin-A supporting role in the skeleton.
"Beginning with mutations in the Lrp5 receptor that control beta-catenin canonical downstream signals, and progressing to transgenic models with bone-specific alteration of beta-catenin, research has shown that beta-catenin is required for normal bone development. A cell critical to bone in which beta-catenin activity determines function is the marrow-derived mesenchymal stem cell (MSC), where sustained beta-catenin prevents its distribution into adipogenic lineage. beta-catenin contributes to control of osteoclastic bone resorption via alteration of the osteoprotegerin/RANKL ratio. The proven ability of mechanical factors to prevent beta-catenin degradation and induce nuclear translocation through Lrp-independent mechanisms suggests processes by which exercise might modulate bone mass via control of lineage allocation, in particular, by preventing precursor distribution into the adipocyte pool."
"Proper regulation of β-catenin signaling is critical for mesenchymal lineage allocation in the developing mouse. Knockout of the APC protein that binds and sequesters β-catenin leads to abnormal skeletal development: use of the Col2a1 promoter allowed Cre-mediated recombination and deletion of APC in osteoblast precursors not yet committed to either the osteoblastic or chondrogenic lineage. This leads to massive β-catenin accumulation in the developing endochondral skeleton and interrupts normal commitment of mesenchymal precursors into both chondrocytic and osteoblastic lineages"
Beta-Catenin is critical for all mesenchymal lineage allocation not just osteogenic. However, eventually Beta-Catenin levels must decrease for proper chondrogenesis.
"β-catenin availability must be restricted at some point for proper osteoblasts to develop, and must be nearly absent for Runx2 expressing cells to enter the chondrocytic lineage."
GSK3Beta, which is inhibited by things like cGKII, interacts with Beta-Catenin.
"Constitutive phosphorylation of β-catenin by cyclin-dependent kinase at serine-45 followed by phosphorylation of the N-terminus by GSK3β targets β-catenin for degradation by the ubiquitin/proteosome pathway, limiting levels of cytoplasmic β-catenin under resting conditions."
Stem cells have the ability to differentiate into adipocytes, osteoblasts, and chondrocytes. Beta-catenin inhibits stem cells from differentiating into adipocytes. Beta-catenin is vital for all mesenchymal stem cells not just ones undergoing an osteogenic lineage.
Role of PI3K on the regulation of BMP2-induced beta-Catenin activation in human bone marrow stem cells.
"Bone morphogenetic protein 2 (BMP2), a very potent bone-inducing agent, promotes the differentiation of bone marrow stem cells (BMSCs) to osteoblasts. In this study, we used a combination of stable isotope labeling by amino acids during cell culture (SILAC) and liquid-chromatography electrospray ionization mass spectrometry (LC-ESI-MS/MS) technology to reveal the BMP2 action in BMSC. In this quantitative proteomic analysis, 414 of 449 proteins were successfully quantified with 79.2% peptide quantification efficiency. Interestingly, beta-Catenin was identified in BMP2-stimulated heavy isotope-labeled cells, and further analysis confirmed that BMP2 increased beta-Catenin mRNA and protein levels. The increment effects of BMP2 on the beta-Catenin expression levels and its translocation to nucleus were diminished by blocking the PI3K signal pathway. In addition, BMP2-induced beta-Catenin activity and ALP activity were blocked by PI3K inhibition. Thus, our quantitative proteomics analysis and further biochemical investigations showed that BMP2 modulates beta-Catenin signaling via PI3K pathway and that this pathway plays roles in BMP2-induced osteoblast differentiation of hBMSCs."
BMP-2 has also been shown to enable differentiation into chondrocytes but BMP-2 also may encourage premature ossification. These traits may extend to Beta-Catenin which is stimulated by BMP-2.
Here's a study that shows that too much Beta-Catenin may cause a reduction in height:
Transient activation of Wnt/{beta}-catenin signaling induces abnormal growth plate closure and articular cartilage thickening in postnatal mice.
"Wnt/beta-catenin signaling is required for skeletal development and organization and for function of the growth plate and articular cartilage. To further clarify these roles and their possible pathophysiological importance, we created a new transgenic mouse model in which Wnt/beta-catenin signaling can be activated in cartilage for specific periods of time. These transgenic mice expressed a constitutive active form of beta-catenin fused to a modified estrogen receptor ligand-binding domain under the control of cartilage-specific collagen 11alpha2 promoter/enhancer[it's possible this wouldn't affect normal Beta-Catenin overexpression, also tamoxifen has shown an increase in apoptosis independent of Beta-Catenin]. Transient Wnt/beta-catenin signaling activation in young adult mice by tamoxifen injections induced growth retardation and severe deformities in knee joints. Tibial and femoral growth plates displayed an excessive number of apoptotic cells and eventually underwent abnormal regression. Articular cartilage exhibited an initial acute loss of proteoglycan matrix that was followed by increases in thickness, cell density, and cell proliferation. In reciprocal studies, we found that conditional ablation of beta-catenin in postnatal mice using a Col2-CreER strategy led to hypocellularity in articular cartilage, growth plate disorganization, and a severe reduction in bone volume."
"acute experimental activation of Wnt/β-catenin signaling strongly stimulates matrix catabolism and protease activity [in chondrocytes]"
"promotes expression of phenotypic traits associated with chondrocyte hypertrophy and replacement with endochondral bone"<-This makes sense as Beta-Catenin stimulates Cyclin D1 which keeps cells in the cell cycle(thus hypertrophying) longer.
"companion chondrocyte cultures were cotransfected with the construct and a dominant-negative β-catenin expression vector, tamoxifen treatment failed to elicit reporter activity, affirming specificity of responses and dependence on β-catenin action."<-They are stating that the tamoxifen effects on apoptosis are specific to Beta-catenin. If Beta-Catenin is overepressed maybe cells keep hypertrophying until they undergo apoptosis and don't exit the cell cycle before that happens. We want Beta-Catenin to be expressed such that cells exit the cell cycle at the last possible second before apoptosis.
"Body length in male and female tamoxifen-treated transgenic mice was reduced approximately 20 to 35% at 7 weeks of age"
"By 7 weeks of age (and 4 weeks from the last tamoxifen injection), the growth plates were nearly absent and had thus undergone abnormal closure"<-Thus no possibility of catch-up growth.
There must be an equilibrium level of Beta-Catenin and if Beta-Catenin gets too high upregulating Sox9 can keep it in check.
Here's a related study to Beta Catenin and chondrogenesis:
Temporal Activation of β-Catenin Signaling in the Chondrogenic Process of Mesenchymal Stem Cells Affects the Phenotype of the Cartilage Generated.
"This study investigated the temporal effect of transforming growth factor (TGF)-β and β-catenin signaling co-activation during MSC chondrogenic differentiation and evaluated the influence of these predifferentiation conditions to subsequent phenotypic development of the cartilage. MSCs were differentiated in chondrogenic medium that contained either TGFβ alone, TGFβ with transient β-catenin coactivation, or TGFβ with continuous β-catenin coactivation. After in vitro differentiation, the pellets were transplanted into SCID mice. Both coactivation protocols resulted in the enhancement of chondrogenic differentiation of MSCs. Compared with TGFβ activation, transient coactivation of TGFβ-induction with β-catenin activation resulted in heightened hypertrophy and formed highly ossified tissues with marrow-like hematopoietic tissue in vivo. The continuous coactivation of the 2 signaling pathways, however, resulted in inhibition of progression to hypertrophy, marked by the suppression of type X collagen, Runx2, and alkaline phosphatase expression, and did not result in ossified tissue in vivo. Chondrocytes of the continuous co-activation samples secreted significantly more parathyroid hormone-related protein (PTHrP) and expressed cyclin D1. Our results suggest that temporal co-activation of the TGFβ signaling pathway with β-catenin can yield cartilage of different phenotype, represents a potential MSC predifferentiation protocol before clinical implantation, and has potential applications for the engineering of cartilage tissue."
"Forced expression of the ligands of β-catenin pathways inhibited embryonic mesenchymal cells condensation and transition to cartilage nodules"
"Wnt3A enhances BMP2-mediated chondrogenesis of murine mesenchymal cells; and in adult human marrow stromal cells, β-catenin activation enhanced TGFβ-induced chondrogenic differentiation"
"The time-dependant increase in ColX protein was accompanied by the gradual increase in Col10 and BSP mRNA"
"the expression of ColX in the continuous co-activation samples was inhibited at all time points, with the complete lack of ColX except for a trace detected in the day 35 sample"
"MSCs that had undergone chondrogenic differentiation with TGFβ treatment secreted an increased level of PTHrP but plateaued by day 14. Cells in the transient co-activation sample secreted similar levels of PTHrP. Comparatively, the level of PTHrP in the continuous co-activation was significantly higher, up to day 21, than both the other groups. Cyclin D1 was differentially expressed in the 3 groups of treatment at differentiation stage of day 21 and day 28, with some donor variability. Even though both pellets of the transient and continuous co-activated groups expressed similar levels of type II collagen, cyclin D1 was not detected in chondrocytes of the transient co-activation pellet, but was prominently expressed in nuclei of most cells in the continuous co-activation pellet. In the TGFβ-treated pellet, chondrocytes in the hypertrophy zone, as marked by the expression of type X collagen, did not express cyclin D1. Instead, cyclin D1 cellular expression was detected in some regions with absence of type X collagen expression. Our data show that the continuous co-activation of TGFβ and β-catenin signaling pathway resulted in heightened secretion of PTHrP and expression of cyclin D1 in the chondrocytes which might have a role in the inhibition of chondrocyte hypertrophy."
"unless chondrogenic differentiation of MSC has been locked in at the appropriate differentiation stage, dedifferentiation of cell and loss of cartilage tissue readily occurred at the ectopic site."
TGF-Beta regulates Beta Catenin.
TGF-β regulates β-catenin signaling and osteoblast differentiation in human mesenchymal stem cells
"Cooperation between transforming growth factor β (TGF-β) and Wnt/β-catenin signaling pathways plays a role in controlling certain developmental events and diseases. Agents like TGF-β, cooperation with Wnt signaling, promote chondrocyte differentiation at the expense of adipocyte differentiation in hMSCs. With selective small chemical kinase inhibitors, we demonstrated that TGF-β1 requires TGFβ type I receptor ALK-5, Smad3, PI3K and PKA to stabilize β-catenin, and needs ALK-5, PKA and JNK to inhibit osteoblastogenesis in hMSCs[since osteoblastogenesis and chondrogenesis can't occur in the same cells this is good for chondrogenesis]. Knockdown of β-catenin with siRNA stimulated alkaline phosphatase activity and antagonized the inhibitory effects of TGF-β1 on bone sialoprotein expression, suggested that TGF-β1 cooperated with β-catenin signaling in inhibitory of osteoblastogenesis in hMSCs."
"After 24 hours, TGF-β1 (1 ng/mL) significantly enhanced β-catenin/TCF/LEF transcription in KM101 cells"<-TGF-Beta1 also upregulates Sox9 which decreases Beta-Catenin complex transcription thus the effects of TGF-Beta1 must be greater than Sox9 on Beta-Catenin. Lithium Chloride also stimulated Beta-Catenin complex.
Alterations in the temporal expression and function of cadherin-7 inhibit cell migration and condensation during chondrogenesis of chick limb mesenchymal cells in vitro.
Alterations in the temporal expression and function of cadherin-7 inhibit cell migration and condensation during chondrogenesis of chick limb mesenchymal cells in vitro.
"Cadherin-7 plays a central role in cellular condensation by modulating cell motility and migration. Many mesenchymal cells failed to migrate, and precartilage condensation was inhibited, after knockdown of endogenous cadherin-7 levels. Exposure of mesenchymal cells to SB203580 (a specific inhibitor of p38MAPK), LiCl (an inhibitor of GSK-3beta) or overexpression of beta-catenin resulted in inhibition of cadherin-7 levels and, subsequently, suppression of cell migration. Collectively, our results suggest that cadherin-7 controls cell migration in chick limb bud mesenchymal cells, and that p38MAPK and GSK signals are responsible for regulating cadherin-7-mediated cell migration."
"Perturbation of N-cadherin inhibits cellular condensation, but its overexpression enhances condensation during chondrogenesis"
"the activity of p38 MAPK increased, while the activity of Erk decreased, as chondrogenesis proceeded. With the progression of chondrogenesis, we also detected very low levels of phosphorylated glycogen synthase kinase-3β (GSK-3β) suggesting inhibition of GSK activity"
BMP-2-enhanced chondrogenesis involves p38 MAPK-mediated down-regulation of Wnt-7a pathway.
"BMP-2 promotes chondrogenesis by activating p38 mitogen-activated protein kinase (MAPK), which in turn downregulates Wnt-7a/b-catenin signaling responsible for proteasomal degradation of Sox9. Exposure of mesenchymal cells to BMP-2 resulted in upregulation of Sox9 protein and a concomitant decrease in the level of b-catenin protein and Wnt-7a signaling. In agreement with this, the interaction of Sox9 with b-catenin was inhibited in the presence of BMP-2. Inhibition of the p38 MAPK pathway using a dominant negative mutant led to sustained Wnt-7a signaling and decreased Sox9 expression, with consequent inhibition of precartilage condensation and chondrogenic differentiation. Moreover, overexpression of b-catenin caused degradation of Sox9 via the ubiquitin/26S proteasome pathway. Our results collectively indicate that the increase in Sox9 protein resulting from downregulation of b-catenin/Wnt-7a signaling is mediated by p38 MAPK during BMP-2 induced chondrogenesis in chick wing bud mesenchymal cell"
Wnt signaling activation during bone regeneration and the role of Dishevelled in chondrocyte proliferation and differentiation.
"all of the Wnt signaling members and target genes analyzed were found to be upregulated during the early stages of fracture repair, with the exception of LEF1 whose expression was downregulated. In addition, spatial expression analysis of Dishevelled (Dvl) and beta-catenin in the fracture callus revealed an identical pattern of expression with both proteins localizing in osteoprogenitor cells of the periosteum, osteoblasts and proliferating/pre-hypertrophic chondrocytes. Further, in vitro knockdown of all three Dvl isoforms in chondrocytes using small interfering RNAs (siRNA) leads to partial inhibition of cell proliferation and differentiation, decreased expression of chondrogenic markers (ColII, ColX, Sox9) and suppressed nuclear accumulation of unphosphorylated beta-catenin. Taken together, these data verify our previous finding that the Wnt signaling pathway is activated during bone regeneration, by characterizing the temporal and spatial expression of a broad spectrum of Wnt-signaling molecules. Our data also suggest that all three Dvl isoforms, acting through the Wnt canonical pathway, are critical regulatory molecules for chondrocyte proliferation and differentiation."
LSJL downregulates Dvl1 which is the most highly expressed Dvl during fracture repair.
"Three members of the mammalian Dvl family (Dvl1, 2, 3) are ubiquitously expressed during all stages of mouse embryogenesis and in most adult tissues with significant overlapping of expression patterns, suggesting that there may be functional redundancy among these three genes"
Genes upregulated in Fracture Bone Regeneration also upregulated in LSJL:
Fzd2
" Dvl is known to induce the dissociation of the GSK3/Axin/β-catenin complex which normally leads to phosphorylation of β-catenin followed by its polyubiquitination and proteosomal degradation"
Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes.
"we show by conditionally deleting beta-catenin in limb and head mesenchyme that beta-catenin is required for osteoblast lineage differentiation. Osteoblast precursors lacking beta-catenin are blocked in differentiation and develop into chondrocytes instead. In vitro experiments demonstrate that this is a cell-autonomous function of beta-catenin in an osteoblast precursor. Furthermore, detailed in vivo and in vitro loss- and gain-of-function analyses reveal that beta-catenin activity is necessary and sufficient to repress the differentiation of mesenchymal cells into Runx2- and Sox9-positive skeletal precursors. Thus, canonical Wnt/beta-catenin signaling is essential for skeletal lineage differentiation, preventing transdifferentiation of osteoblastic cells into chondrocytes."
"hypertrophic chondrocytes mineralized and were degraded, resulting in accumulation of their mineralized matrix, although no trabecular bone and no bone collar were formed [in beta-catenin knock out]."
In Vivo Analysis of Wnt Signaling in Bone
Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes.
"we show by conditionally deleting beta-catenin in limb and head mesenchyme that beta-catenin is required for osteoblast lineage differentiation. Osteoblast precursors lacking beta-catenin are blocked in differentiation and develop into chondrocytes instead. In vitro experiments demonstrate that this is a cell-autonomous function of beta-catenin in an osteoblast precursor. Furthermore, detailed in vivo and in vitro loss- and gain-of-function analyses reveal that beta-catenin activity is necessary and sufficient to repress the differentiation of mesenchymal cells into Runx2- and Sox9-positive skeletal precursors. Thus, canonical Wnt/beta-catenin signaling is essential for skeletal lineage differentiation, preventing transdifferentiation of osteoblastic cells into chondrocytes."
"hypertrophic chondrocytes mineralized and were degraded, resulting in accumulation of their mineralized matrix, although no trabecular bone and no bone collar were formed [in beta-catenin knock out]."
In Vivo Analysis of Wnt Signaling in Bone
"activating and inactivating mutations in low-density lipoprotein receptor-related protein 5, a putative Wnt coreceptor, led to high bone mass and low bone mass in human beings"
"Axial skeletal truncation [was] found in Wnt3a−/− mice and limb patterning defects [were] observed in Wnt7a−/− mice"
"Inactivation of β-catenin using α1(II) collagen-Cre, Dermo1-Cre, or Prx1-Cre mice leads to ectopic chondrocyte formation at the expense of osteoblast differentiation, during both endochondral and intramembranous ossification"
"Ectopic Wnt signaling in chondrocytes via α1(II)-collagen-Wnt14 transgenic mice enhances ossification and suppresses chondrogenesis."
"High levels of canonical Wnt signaling (as determined by levels of β-catenin) with the presence of Runx2 promote osteoblastogenesis at the expense of chondrocyte differentiation. In contrast, low levels of β-catenin along with the presence of Sox9 lead to chondrocyte differentiation without supporting osteoblastogenesis"
"Secreted frizzled receptor proteins (Sfrps) are another class of Wnt antagonists. Sfrp1 is highly expressed during the transition from preosteoblast to osteoblast. Sfrp1−/− mice have an increase in trabecular but not cortical bone, and this increase is more elevated in female mice. Sfrp1−/− mice also have shortened growth plates and increased calcification of the hypertrophic zone of chondrocytes, indicating increased chondrocyte differentiation and endochondral ossification. Therefore, Sfrp1 may serve as a negative regulator of both osteogenesis and chondrogenesis."
"Ror2−/− mice have several skeletal abnormalities that are attributable to cartilage and growth plate defects"
Mechanical loading regulates NFATc1 and beta-catenin signaling through a GSK3beta control node.
So if mechanical loading induces ectopic chondrocyte formation it likely doesn't do it through reducing beta-catenin signaling. Although LSJL and axial loading initiate many other types of strain than straight mechanical loading.
"Mechanical stimulation can prevent adipogenic and improve osteogenic lineage allocation of mesenchymal stem cells (MSC), an effect associated with the preservation of beta-catenin levels. We asked whether mechanical up-regulation of beta-catenin was critical to reduction in adipogenesis as well as other mechanical events inducing alternate MSC lineage selection. In MSC cultured under strong adipogenic conditions, mechanical load (3600 cycles/day, 2% strain) inactivated GSK3beta in a Wnt-independent fashion. Small interfering RNA targeting GSK3beta prevented both strain-induced induction of beta-catenin and an increase in COX2, a factor associated with increased osteoprogenitor phenotype. Small interfering RNA knockdown of beta-catenin blocked mechanical reduction of peroxisome proliferator-activated receptor gamma and adiponectin, implicating beta-catenin in strain inhibition of adipogenesis. In contrast, the effect of both mechanical and pharmacologic inhibition of GSK3beta on the putative beta-catenin target, COX2, was unaffected by beta-catenin knockdown. GSK3beta inhibition caused accumulation of nuclear NFATc1; mechanical strain increased nuclear NFATc1, independent of beta-catenin. NFATc1 knockdown prevented mechanical stimulation of COX2, implicating NFATc1 signaling. Finally, inhibition of GSK3beta caused association of RNA polymerase II with the COX2 gene, suggesting transcription initiation. These results demonstrate that mechanical inhibition of GSK3beta induces activation of both beta-catenin and NFATc1 signaling, limiting adipogenesis via the former and promoting osteoblastic differentiation via NFATc1/COX2."
"Axial skeletal truncation [was] found in Wnt3a−/− mice and limb patterning defects [were] observed in Wnt7a−/− mice"
"Inactivation of β-catenin using α1(II) collagen-Cre, Dermo1-Cre, or Prx1-Cre mice leads to ectopic chondrocyte formation at the expense of osteoblast differentiation, during both endochondral and intramembranous ossification"
"Ectopic Wnt signaling in chondrocytes via α1(II)-collagen-Wnt14 transgenic mice enhances ossification and suppresses chondrogenesis."
"High levels of canonical Wnt signaling (as determined by levels of β-catenin) with the presence of Runx2 promote osteoblastogenesis at the expense of chondrocyte differentiation. In contrast, low levels of β-catenin along with the presence of Sox9 lead to chondrocyte differentiation without supporting osteoblastogenesis"
"Secreted frizzled receptor proteins (Sfrps) are another class of Wnt antagonists. Sfrp1 is highly expressed during the transition from preosteoblast to osteoblast. Sfrp1−/− mice have an increase in trabecular but not cortical bone, and this increase is more elevated in female mice. Sfrp1−/− mice also have shortened growth plates and increased calcification of the hypertrophic zone of chondrocytes, indicating increased chondrocyte differentiation and endochondral ossification. Therefore, Sfrp1 may serve as a negative regulator of both osteogenesis and chondrogenesis."
"Ror2−/− mice have several skeletal abnormalities that are attributable to cartilage and growth plate defects"
Mechanical loading regulates NFATc1 and beta-catenin signaling through a GSK3beta control node.
So if mechanical loading induces ectopic chondrocyte formation it likely doesn't do it through reducing beta-catenin signaling. Although LSJL and axial loading initiate many other types of strain than straight mechanical loading.
"Mechanical stimulation can prevent adipogenic and improve osteogenic lineage allocation of mesenchymal stem cells (MSC), an effect associated with the preservation of beta-catenin levels. We asked whether mechanical up-regulation of beta-catenin was critical to reduction in adipogenesis as well as other mechanical events inducing alternate MSC lineage selection. In MSC cultured under strong adipogenic conditions, mechanical load (3600 cycles/day, 2% strain) inactivated GSK3beta in a Wnt-independent fashion. Small interfering RNA targeting GSK3beta prevented both strain-induced induction of beta-catenin and an increase in COX2, a factor associated with increased osteoprogenitor phenotype. Small interfering RNA knockdown of beta-catenin blocked mechanical reduction of peroxisome proliferator-activated receptor gamma and adiponectin, implicating beta-catenin in strain inhibition of adipogenesis. In contrast, the effect of both mechanical and pharmacologic inhibition of GSK3beta on the putative beta-catenin target, COX2, was unaffected by beta-catenin knockdown. GSK3beta inhibition caused accumulation of nuclear NFATc1; mechanical strain increased nuclear NFATc1, independent of beta-catenin. NFATc1 knockdown prevented mechanical stimulation of COX2, implicating NFATc1 signaling. Finally, inhibition of GSK3beta caused association of RNA polymerase II with the COX2 gene, suggesting transcription initiation. These results demonstrate that mechanical inhibition of GSK3beta induces activation of both beta-catenin and NFATc1 signaling, limiting adipogenesis via the former and promoting osteoblastic differentiation via NFATc1/COX2."
"MSC are highly responsive to mechanical signals during differentiation"
Roles of Wnt/β-catenin signalling pathway in the bony repair of injured growth plate cartilage in young rats.
Roles of Wnt/β-catenin signalling pathway in the bony repair of injured growth plate cartilage in young rats.
"Wnt-β-catenin signalling pathway [regulates] growth plate repair and the pathway [plays] a crucial role in the osteogenic differentiation of mesenchymal progenitor cells, the current study investigated the bony repair of injured tibial growth plate in rats. β-catenin immunopositive cells [occurred] within the growth plate injury site. Treatment of the injured rats with the β-catenin inhibitor ICG-001 (oral gavage[forced feeding] at 200mg/kg/day for 8days, commenced at day 2 post injury) enhanced COL2A1 gene expression and increased proportion of cartilage tissue, but decreased level of osterix expression and amount of bone tissue, at the injury site by day 10 post-injury (n=8). Bone marrow stromal cells from normal rats showed that β-catenin inhibitor ICG-001 dose dependently inhibited expression of Wnt target genes Cyclin D1 and survivin. At 25mM, ICG-001 suppressed osteogenic but enhanced chondrogenic differentiation. These results suggest that Wnt/β-catenin signalling pathway is involved in regulating growth plate injury repair by promoting osteoblastogenesis, and that intervention of this signalling could represent a potential approach in enhancing cartilage repair after growth plate injury."
"Skeletal injuries activate endogenous Wnt signalling, triggering a cascade of events leading to the expansion of the skeletal stem/progenitor pool [and] bone formation"
"6-week-old male Sprague Dawley rats"
"Injury was inflicted using the drill-hole method, disrupting the central part of the proximal tibial growth plate cartilage"
Loss of β-Catenin Induces Multifocal Periosteal Chondroma-Like Masses in Mice.
Loss of β-Catenin Induces Multifocal Periosteal Chondroma-Like Masses in Mice.
"Osteochondromas and enchondromas are the most common tumors affecting the skeleton. Osteochondromas can occur as multiple lesions, such as those in patients with hereditary multiple exostoses. Conditional deletion [of Beta-Catenin] induces ectopic chondroma-like cartilage formation in mice. Postnatal ablation of β-catenin in cartilage induced lateral outgrowth of the growth plate within 2 weeks after ablation. The chondroma-like masses were present in the flanking periosteum by 5 weeks and persisted for more than 6 months after β-catenin ablation. These long-lasting ectopic masses rarely contained apoptotic cells. In good correlation, transplants of β-catenin-deficient chondrocytes into athymic mice persisted for a longer period of time and resisted replacement by bone compared to control wild-type chondrocytes. In contrast, a β-catenin signaling stimulator increased cell death in control chondrocytes. The amount of detectable β-catenin in cartilage cells of osteochondromas obtained from hereditary multiple exostoses patients was much lower than that in hypertrophic chondrocytes in normal human growth plates. Loss of β-catenin expression in chondrocytes induces periosteal chondroma-like masses and may be linked to, and cause, the persistence of cartilage caps in osteochondromas."
"PTHR1 mutations caused constitutive activation of hedgehog signaling in cultured chondrocytes and that overexpression of Gli2, a downstream molecule of hedgehog signaling, induced enchondromas in mice."<-an enchondroma is a cartilage cyst in the bone marrow.
"Mutations in EXT1 and EXT2 genes have been associated with HME (multiple osteochondroma){a tumor that is a mix of cartilage and bone}. Mutations in these genes are often missense or frame shift and cause synthesis of lower levels of (and shorter) heparan sulfate chains. This is because EXT1 and EXT2 encode Golgi-associated enzymes are responsible for the polymerization of the chains. Insufficiency of heparan sulfate-rich proteoglycans is thought to be a cause of osteochondroma formation. Heparan sulfate proteoglycans are important for the regulation of many signaling pathways that include hedgehog, bone morphogenetic protein, fibroblast growth factor, and Wnt pathways. All of these pathways are critical regulators for chondrogenic differentiation and chondrocyte differentiation. It is likely that dysregulation of these signaling pathways resulting from heparan sulfate deficiency may trigger abnormal behavior of growth plate chondrocytes or induce ectopic chondrogenic differentiation, leading to ectopic cartilage formation."
"[Beta-Catenin deficient] mice developed ectopic cartilaginous masses located near the bone surface but not within the bone marrow"<-if they developed ectopic cartilaginous masses within the bone marrow that would be really nice for proving LSJL.
"β-catenin-deficient cells autonomously form the ectopic cartilage masses and could originate from the growth plate."
"Ectopic cartilage originates via abnormal expansion of the growth plate into the lateral site of perichondrium and is eventually embedded within the periosteum with time. It is therefore likely that ectopic cartilage formation is largely induced by abnormal behavior and function of growth plate chondrocytes in our models. However, we cannot exclude the possibility that neodifferentiation of perichondrium or periosteum-associated skeletal progenitor cells into chondrocytes may also contribute to ectopic cartilage formation."
There were some supplementary figures that I could not access as of yet.
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