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The rat bone/liver/kidney/placenta (BLKP) alkaline phosphatase (ALP) gene is expressed at high level in these particular tissues and at low levels in many other tissues. To study the mechanisms underlying the complex regulation of the rat BLKP ALP expression, we isolated a genomic clone, containing a 10.5-kb insert, which includes the promoter of the BLKP ALP gene with 2kb of 5' flanking region, its first exon (84bp), and over 7kb of the first intron. The promoter of the rat BLKP ALP displays features of a “housekeeping” gene promoter: an atypical TATA-box (TTCATAA); 3 potential Spl binding sites; high GC content (82% in positions -134 to -14); and a high CpG to GpC ratio (60:89 in the 0.85-kb promotor region), indicating an abundance of potential methylation sites. Likewise, transient transfection of CAT fusion genes into ROS 17/2.8 osteoblast-like cells reveals weak expression from the promoter and proximal 5' flanking sequences, which can be elevated by an SV40 E enhancer. The homologous human bone/liver/kidney (BLK) ALP promoter, which demonstrates a similar combination of tissue-specific and housekeeping characteristics, shares close similarity (184bp of 79% similarity excluding gaps) with the rat BLKP ALP promoter. The human placental ALP is encoded by a separate gene and its promoter, on the other hand lacks significant similarity to the rat BLKP ALP promoter despite their common expression in the placenta. This lack of similarity appears to reflect the close evolutionary relationship of the human placental ALP gene to the intestinal ALP gene. Significant sequence similarity was found between the rat and human BLK/BLKP ALP promoters and the human and mouse adenine deaminase promoters, and together they may represent a class of dual-function promoters, allowing both constitutive low-level, and tissuespecific higher levels of expression. A pentanucleotide with the consensus sequence 5'-GGCTC-3' is present in these promoters and in the promoters for the human fibronectin and the human α1(II) pro collagen genes in the region of maximal similarity with the rat BLKP ALP promoter, and in the vicinity of the Sp1-binding sites.

As a member of the nitrogen-containing bisphosphonates (N-BPs), alendronate (ALN), marketed as Fosamax (alendronate sodium trihydrate), was the first potent and highly effective nonhormonal antiosteoporotic agent available for clinical use. The high potency of ALN (70 mg, by month once weekly), which comes despite its very low bioavailability (

The role of 3′5′-cyclic AMP (cAMP) in the release from dormancy of gemmules from the freshwater sponge Spongilla lacustris was investigated. During the first 2 hr of germination a significant decrease in the gemmule cAMP content was observed. In the presence of amino-phylline, at concentrations which inhibit the gemmule-cAMP-phosphodiesterase, the cAMP content did not decrease and germination was arrested at a stage prior to nuclear separation and cell division. The findings suggest that inhibition of cell division by cAMP participates in the control of dormancy.

indirect effect of decreased cartilage damage on aberrant bone remodeling. Conclusions: The dual goals of translation research are to discover novel disease mechanisms and to transform this information into new therapeutics for human disorders. Here we present data that implicate cysteinyl leukotrienes in early OA progression. Therefore, targeting of this pathway could represent an important area to OA research and treatment. In addition, the apparent similarities of the DMM model to humans at risk for OA from meniscal damage, suggests that treatment proximal to the time of meniscal repair with CysLT antagonists could delay the structural progression of incipient OA. Subchondral bony sclerosis is a contributing co-factor in OA progression. Although, the reduction in cartilage damage observed in this study could be seen as the most clinically relevant outcome for montelukast treatment of OA, prevention of abnormal bone remodeling could have equally important outcomes in OA joint prophylaxis. 528