Proteinase-activated receptor-2 (PAR2) and mouse osteoblasts: Regulation of cell function and lack of specificity of PAR2- activating peptides

Smitha R Georgy, Charles N Pagel, David M Wong, Sutharshani Sivagurunathan, Lay H Loh, Damian E Myers, Morley D Hollenberg, Robert Neil Pike, Eleanor J Mackie

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Summary 1. Using synthetic PAR(2)-activating peptides (PAR(2)APs) corresponding to the tethered ligand domain of PAR(2) s extracellular N-terminus to mimic the actions of activating proteinases and employing primary cultures of calvarial osteoblasts derived from both wild-type (WT) and PAR(2)-null (KO) mice, we investigated the potential role of PAR(2) in regulating osteoblast function. 2. Primary calvarial osteoblasts from WT and KO animals were evaluated for their growth kinetics and mineralisation in the absence of PAR(2) agonists and for their responses in a variety of functional assays to the PAR(2)APs, Ser-Leu-Ile-Gly-Arg-Leu-amide (SLIGRL-NH(2)) and 2-furoyl-Leu-Ile-Gly-Arg-Leu-Orn-amide (2-fLIGRLO-NH(2)) and to trypsin. 3. In contrast to the WT cells, PAR(2) KO osteoblasts did not exhibit increased collagen type I mRNA expression in response to SLIGRL-NH(2). When grown in serum-containing medium, KO cells increased in number more rapidly than WT cultures, an effect that could be attributed to decreased apoptosis rather than increased proliferation. Surprisingly, in both WT and KO osteoblasts, the two PAR(2)APs induced mobilisation of intracellular calcium stores. Similarly, PAR(2)APs inhibited serum deprivation-induced apoptosis and parathyroid hormone-, 1,25 dihydroxyvitamin D(3)- or interleukin-11-induced mineralisation in WT and KO cells. 4. We conclude that PAR(2) plays a role in osteoblast survival and collagen type I mRNA induction and that osteoblasts can respond to the PAR(2)APs by both a PAR(2)-dependent and a PAR(2)-independent mechanism.
Original languageEnglish
Pages (from-to)328 - 336
Number of pages9
JournalClinical and Experimental Pharmacology and Physiology
Issue number3
Publication statusPublished - 2010

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