Saturday, February 18, 2012


F-Spondin which decreases height also increases MMP13.

Role of matrix metalloproteinase 13 in both endochondral and intramembranous ossification during skeletal regeneration.

"MMP13 is required for proper resorption of hypertrophic cartilage and for normal bone remodeling during non-stabilized fracture healing, which occurs via endochondral ossification. However, no difference in callus strength was detected in the absence of MMP13. Transplant of wild-type bone marrow, which reconstitutes cells only of the hematopoietic lineage, did not rescue the endochondral repair defect, indicating that impaired healing in Mmp13-/- mice is intrinsic to cartilage and bone. Mmp13-/- mice also exhibited altered bone remodeling during healing of stabilized fractures and cortical defects via intramembranous ossification. The bone phenotype occurs independently from the cartilage phenotype. MMP13 is involved in normal remodeling of bone and cartilage during adult skeletal repair, and that MMP13 may act directly in the initial stages of ECM degradation in these tissues prior to invasion of blood vessels and osteoclasts."

"MMP13 promotes both the resorption of hypertrophic cartilage from the growth plate and the remodeling of newly deposited trabecular bone during long bone development"

" At 3 days post-[non-stabilized]-fracture, we observed Mmp13 expression in regions of activated periosteum that also expressed Col1"

"At 6 days post-fracture, we observed Mmp13-expressing cells within the Col1 expression domain in Osteocalcin (Oc)-negative portions of the periosteum, indicating that Mmp13 is expressed during the early stages of healing by immature osteoblasts. The Mmp13 expression pattern differed from that of Mmp9, indicating that Mmp13 was not upregulated in newly recruited inflammatory cells and osteoclasts"

"At 10 days post-fracture, Mmp13 expression in the cartilage overlapped with Col10 and Vascular endothelial growth factor (Vegf) expression, indicating that Mmp13 is expressed by hypertrophic and late hypertrophic chondrocytes. At 14 days post-fracture, Mmp13 expression colocalized with Col1 and Oc expression, suggesting that by this time point Mmp13 is expressed in both immature and mature osteoblasts within the callus. Mmp13 expression was detected in osteoblasts throughout the remodeling phase of healing and was not associated with osteoclasts"

"the expression pattern of Mmp13 in both cartilage and bone tissues during fracture healing parallels that seen during development via endochondral ossification"

"there was a significantly greater volume of cartilage and of cartilage as a proportion of total callus volume in Mmp13−/− calluses at 7, 14 and 21 days post-fracture"

"At 28 days post-fracture, there was a significantly greater volume of spongy bone in Mmp13−/− calluses as compared to WT "<-But no difference in compact bone volume.

" Mmp9−/− mice, display aberrant cartilage formation at 10 days post-[stabilized]-fracture. Mmp13−/− stabilized fracture calluses did not display cartilage and were comparable to WT"

"[At 28 days], Mmp13−/− stabilized fracture calluses, were larger and contained more bone as compared to WT."

"the absence of MMP13 does not affect the overall amount of cartilage produced in the callus during non-stabilized fracture healing, but rather affects the removal of hypertrophic cartilage from the callus."<-So this is why MMP13 likely does not reduce but rather can increase height.

"MMP9 is strongly expressed by osteoclasts in the fracture callus, we observed that MMP13 was confined to chondrocytes and osteoblasts"

Knee loading reduces MMP13 activity in the mouse cartilage.

"Knee loading (0.5--3 N for 5 min) was applied to the right knee of surgically-induced osteoarthritis (OA) mice as well as normal (non-OA) mice, and MMP13 activity in the femoral cartilage was examined. The sham-loaded knee was used as a non-loading control. We also employed primary non-OA and OA human chondrocytes as well as C28/I2 chondrocyte cells, and examined MMP13 activity and molecular signaling in response to shear at 2--20 dyn/cm2.
Daily knee loading at 1 N for 2 weeks suppressed cartilage destruction in the knee of OA mice. Induction of OA elevated MMP13 activity and knee loading at 1 N suppressed this elevation. MMP13 activity was also increased in primary OA chondrocytes, and this increase was attenuated by applying shear at 10 dyn/cm2. Load-driven reduction in MMP13 was associated with a decrease in the phosphorylation level of p38 MAPK (p-p38) and NFkappaB (p-NFkappaB). Molecular imaging using a fluorescence resonance energy transfer (FRET) technique showed that Rac1 activity was reduced by shear at 10 dyn/cm2 and elevated by it at 20 dyn/cm2. Silencing Rac1 GTPase significantly reduced MMP13 expression and p-p38 but not p-NFkappaB. Transfection of a constitutively active Rac1 GTPase mutant increased MMP13 activity, while a dominant negative mutant decreased it.
Knee loading reduces MMP13 activity at least in part through Rac1-mediated p38 MAPK signaling."

LSJL was done in this study.

"Dynamic deformations of the epiphysis cause alterations in fluid pressure in the intramedullary cavity, driving oscillatory fluid flow and molecular transport in the lacunocanalicular network in the bone matrix and in the medullary cavity. Fluid flow may cause shear stress to osteocytes, leading to osteoblast differentiation and the initiation of bone formation"

"knee loading was applied at three levels of 0.5 N (mild), 1 N (moderate), and 3 N (strong), and fluid flow was given to induce shear intensity of 2 and 5 dyn/cm2 (mild), 10 dyn/cm2 (moderate), and 20 dyn/cm2 (strong)."

Loading+OA did not increase BMC or BMD anymore than control levels.

"MMP13 activity was decreased by 13% and 16% in response to loads at 0.5 N and 1 N, respectively. At the higher loads of 3 N, however, load-driven reduction of MMP13 was not observed"

"Loads at 0.5 and 1 N decreased the phosphorylated levels of p38 and NFκB in a load intensity-dependent manner. The reduction of their phosphorylation levels was larger at 0.5 N than at 1 N. Loads at 3 N, however, did not lower the levels of p-p38, and they increased the level of p-NFκB. "

"In C28/I2 chondrocyte cells, RNA interference with Rac1 siRNA significantly decreased the level of p-p38, but it did not alter the level of p-NFκB"

"Although oscillatory compressive stress at 0.2–0.5 atmospheric pressure (2–5 × 105 dyn/cm2) was also able to reduce the levels of MMP13 mRNA and p-p38 in C28/I2 chondrocyte cells, cells were ~105 times more sensitive to shear stress than compressive stress"

"Rac1 is necessary for development and maintenance of cartilage, and its chondrocyte-specific deletion results in severe dwarfism in mice. In response to fibronectin fragments, it is reported that Rac1 is required for the production of MMP13 in chondrocytes"

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