MMP3

LSJL upregulates MMP3.

Overgrowth with increased proliferation of fibroblast and matrix metalloproteinase activity related to reduced TIMP1: a newly recognized syndrome?

"We report on a child with prenatal onset of overgrowth associated with thick, excessive wrinkled skin and other abnormalities including cleft palate, Chiari malformation and polymicrogyria. His clinical features do not resemble any of the known reported overgrowth syndromes. Genetic evaluations, including karyotype, oligoarray, methylation-sensitive multiplex ligation-dependent probe amplification (MLPA) for 11p11.2 region, CDKN1C sequencing, GPC3 sequencing and dosage analysis, and HRAS sequencing, have been un-revealing. Immunohistochemistry done on the patient's cultured skin fibroblasts showed normally assembled elastic fibers and normal pattern of chondroitin sulfate deposition with defective deposition of Collagen I fibers. In addition, there were high levels of immuno-detectable metalloproteinase 3 (MMP3) and undetectable tissue inhibitor of metalloproteinase 1 (TIMP1){up}. The defective collagen deposition in the fibroblast culture could be reversed by the broad spectrum MMP inhibitor, doxycycline. fibroblasts of this patient have an increased rate of cellular proliferation. We propose that this is a previously unrecognized overgrowth syndrome associated with increased cellular proliferation and defective collagen I deposition due to an imbalance between MMP and TIMP in fibroblasts."

"His birth weight was 4,640 g, length 56.5 cm, and head circumference 38.5 cm (all above 97th centile)."

"patient fibroblasts proliferated faster than normal control counterparts and often formed clusters containing less chondroitin sulfate deposited between individual cells."

It's unclear whether this syndrome induces overgrowth after the neonatal stage.

Since LSJL upregulates MMP3 and TIMP1 perhaps a TIMP1 inhibitor would produce similar overgrowth in the bone.

The increase in p-Akt in LSJL

It has been found LSJL increases Akt phosphorylation.  Now where does that increase occur?  In the stem, cells, bone or cartilage.  Ideally, we'd want it to be to increased in the stem cells which would be indicative of ectopic chondrossification.


Akt phosphorylation in human chondrocytes is regulated by p53R2 in response to mechanical stress.

"The p53 tumor-suppressor protein p53R2 is activated in response to various stressors that act on cell signaling. When DNA is damaged, phosphorylation of p53 at its Ser 15 residue induces p53R2 production. The role of p53R2 in chondrocytes remains poorly understood. In this study, we evaluated in chondrocytes, p53R2 expression and its regulation in response to mechanical stress. Furthermore, we investigated the function of p53R2 in relation to mechanotransduction.

Osteoarthritis (OA) cartilage obtained from total knee replacements and normal cartilage obtained from femoral neck fractures was used to measure p53R2 expression. The OA chondrocytes were subjected to a high magnitude of cyclical tensile strain by using an FX-2000 Flexercell system. Next, sulfated glycosaminoglycan (sGAG) production was quantified in these cells. Protein expression of p53R2, and phosphorylation of Akt, p38MAPK, ERK1/2, and JNK was also detected. Akt phosphorylation was detected after transfecting the cells with p53R2-specific small interfering RNA (siRNA).

Expression of p53R2 was significantly increased in OA chondrocytes and in chondrocytes after applying 5% tensile strain to the cells. However, Akt phosphorylation was down-regulated in OA chondrocytes after the strain, and was up-regulated after transfection of p53R2. sGAG protein as well as collagen type II and aggrecan mRNA{both up in LSJL} was increased following transfection of p53R2-specific siRNA after 5% tensile strain.

p53R2 could regulate matrix synthesis via Akt phosphorylation during chondrocyte mechanotransduction."

"The ribonucleotide reductase (RR) small subunit 2 homolog p53R2 is directly regulated by p53 during the supply of nucleotides for the repair of damaged DNA "

"p53R2 interacts with MEK2, the extracellular signal-regulated kinase (ERK) kinase 2-mitogen-activated protein kinase (MAPK) 2, and the molecule immediately upstream of ERK in the Ras–Raf–MAPK signaling cascade. p53R2 negatively modulates serum-induced MEK–ERK activity"