Bone fracture repair, but not fetal skeletal development is supported by syndecan-4.
"We used Sdc4-/- mice to analyze the functional role of Scd4 in endochondral ossification of mouse embryos and in adult fracture repair. In Sdc4-/-/LacZ knock-in animals, Sdc4 promoter activity was detectable in all stages of chondrocyte differentiation, and Sdc4 deficiency inhibited chondrocyte proliferation. Aggrecan turnover in the uncalcified cartilage of the epiphysis was decreased transiently in vivo, but this did not lead to a growth phenotype at birth. By contrast, fracture healing in adult mice was markedly delayed in Sdc4-/- animals and accompanied by increased callus formation. Blocking inflammation during fracture healing with a TNFα inhibitor reduced these changes in Sdc4-/- animals to WT levels. Analysing the discrepancy between the mild embryonic and the severe adult phenotype, we found a compensatory up-regulation of Sdc2{down} in the developing cartilage of Sdc4-/- mice that was absent in adult tissue. Stimulation of chondrocytes with Wnt3a in vitro, led to an increased expression of Sdc2, while stimulation with TNFα resulted in an up-regulation of Sdc4 but a decreased expression of Sdc2. TNFα stimulation decreased Sdc2- and increased Sdc-4 expression even in presence of Wnt3a, suggesting a strong effect of inflammation on the regulation of Sdc expression."
The upregulation of Sdc4 and downregulation of Sdc2 is consistent with the inflammatory role in fracture repair thus providing evidence that inflammation is involved in the LSJL response.
"Expression of Sdc1, -2 and -4 has been detected in chondrocytes and progenitor cells during development of rat mandibular condyles. Sdc3 has been implicated in regulating the size of skeletogenic condensations and growth factor-mediated proliferation of chondrocytes during limb development and growth. In addition, Sdc2 and -4 are involved in osteoblast cell adhesion and survival"
"At the cellular level, Sdc4 promoter activity was seen throughout the cartilage of the epiphysis and in resting, proliferating, prehypertrophic and hypertrophic chondrocytes within the epiphyses"
"a substantially reduced staining for ADAMTS-4{up in LSJL} protein was detected throughout the cartilage in Sdc4-/- E16.5 tibia in comparison with wild type cartilage"
"Sdc2 expression during development is most likely induced by Wnt3a, a growth factor that is involved in the transition of mesenchymal cells into chondroprogenitor cells"
"stimulation of WT chondrocytes with 100 ng/ml Wnt3a in vitro led to increased Sdc2 mRNA levels (3 fold up-regulation). In contrast TNFα stimulation decreased Sdc2 mRNA levels in a dose dependent manner by up to 50 %"
Sdc4 and Sdc2 regulation are likely highly involved in the LSJL response.
Sdc2 mRNA levels in a dose dependent manner by up to 50 %"
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