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Mechanical strain plays a crucial role in bone remodeling during growth and development and healing of bone besides systemic and local factors. One of the major factors involves in remodeling process is matrix metalloproteinases (MMPs) such as MMP-13 that has been shown to degrade the native interstitial collagens in several tissues. To study how mechanical strain affects extracellular matrix degradation by MMP-13, a biaxial strain was applied to MC3T3-E1 osteoblastic cells plated onto a collagen-coated flexible elastic membrane. The MMP-13 protein and mRNA expression were determined by Western blotting and reverse transcriptase-PCR, respectively. The zymographic activities of MMP-13 increased dramatically at 30 min, reached a peak by 2-fold at 1 h, and maintained up to 4 h. Moreover, the MMP-13 and c-fos mRNA expressed at 5 min, increased to 2.8-and 3-fold at 1 h, respectively, and gradually declined thereafter. Cycloheximide and actinomycin D did not inhibit the MMP-13 and c-fos mRNA expression, suggesting that such expression does not require de novo protein synthesis and not change their stabilities. To investigate which of the mitogen-activated protein kinase (MAPK) pathways involves in the expression of MMP-13, inhibitors such as PD98059, SB203580, and SP600125 were used. However, only PD98059 (an inhibitor of MEK1/2 activation) inhibited MMP-13 and c-fos gene expression; the result was further substantiated by transfecting with the dominant negative mutants of MEK1/2 (MEK K97R) and ERK2. Taken together, our results showed that mechanical strain induces the MMP-13 expression through MEK-ERK signaling pathway to regulate mechanical adaptation.Bone is constantly remodeled throughout life to meet the functional demands of its physiological and mechanical environment (1-4). Remodeling of bone is regulated by a wide variety of systemic and local factors such as 1␣,25-dihydeoxyvitamin D 3 , parathyroid hormone, calcitonin, sex hormones, prostaglandin, transforming growth factor-␤, bone morphogenetic protein, and insulin-like growth factors. It is also a well known fact during growth and in the adult skeleton, a moderate level of mechanical loading is considered essential for maintaining and adaptation to the physiological bone remodeling (4, 5). In particular, mechanical loading on osteoblasts in vitro has been demonstrated to increase prostaglandin release (6), stimulate cell division (7), alter collagen synthesis (8), and promote collagenase activity (9).The remodeling of the mineralized connective tissue involves coupling of the degradation of the extracellular matrix (ECM) 1 with the synthesis of new matrix components. Although osteoblasts have been implicated only in bone formation, in response to resorption stimulators, they may cease synthesis of collagen and start secreting neutral proteinases such as collagenase (10 -12). These collagenases may degrade the unmineralized osteoid layer covering bone surfaces, leading to the exposure of the mineralized matrix to osteoclasts. On the other hand, recent findi...

Background: , which is highly up-regulated in oral cancer cells, has been reported to be aberrantly expressed in several cancers; however, the significance of miR-196 in oral cancer has not yet been addressed.

Fibroblast activation protein (FAP) belongs to the prolyl peptidase family. FAP inhibition is expected to become a new antitumor target. Most known FAP inhibitors often resemble the dipeptide cleavage products, with a boroproline at the P1 site; however, these inhibitors also inhibit DPP-IV, DPP-II, DPP8, and DPP9. Potent and selective FAP inhibitor is needed in evaluating that FAP as a therapeutic target. Therefore, it is important to develop selective FAP inhibitors for the use of target validation. To achieve this, optimization of the nonselective DPP-IV inhibitor 8 led to the discovery of a new class of substituted 4-carboxymethylpyroglutamic acid diamides as FAP inhibitors. SAR studies resulted in a number of FAP inhibitors having IC(50) of <100 nM with excellent selectivity over DPP-IV, DPP-II, DPP8, and DPP9 (IC(50) > 100 μM). Compounds 18a, 18b, and 19 are the only known potent and selective FAP inhibitors, which prompts us to further study the physiological role of FAP.

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