The association between mechanical stimulation and chondrocyte homeostasis has been reported. However, the participation of PTHrP (parathyroid-hormone-related protein) in the mechano-regulation of chondrocyte metabolism remains unclear. We determined whether mechanical stimulation of chondrocytes induces the expression of PTHrP and, further, whether the mechano-modulation of PTHrP is dependent on the maturational status of chondrocytes. Cyclic mechanical strain was applied to rat growth plate chondrocytes at the proliferating, matrix-forming, and hypertrophic stages at 30 cycles/min. Cyclic mechanical strain significantly increased PTHrP mRNA levels in chondrocytes at the proliferating and matrix-forming stages only. The induction of PTHrP was dependent on loading magnitude at the proliferating stage. Using specific ion channel blockers, we determined that mechano-induction of PTHrP was inhibited by nifedipine, a Ca2+ channel blocker. These results suggest that mechanical induction of PTHrP possibly provides the environment for greater chondrocyte replication and matrix formation that would subsequently affect cartilage formation.

This study demonstrates that specific FN fragments are markers for periodontal disease status and supports the role of FN fragments as potential components in the pathogenesis of periodontal disease.

The extracellular matrix regulates many cellular processes, including survival, and alterations in the matrix or in matrix survival signals can trigger apoptosis. Previously, we showed that an altered fibronectin matrix triggers apoptosis in primary cells via a novel pathway regulated by transcriptionally mediated decreases in p53 and c-Myc levels. Here we report that this apoptotic mechanism is propagated by decreased phosphorylation of focal adhesion kinase (FAK), which is linked to increased phosphorylation of c-Jun N-terminal kinase (JNK) and to decreased levels of p53. FAK is physically and spatially linked to JNK and p53, which relocalize from the nucleus to the cell membrane to mediate this interaction. Further, p53 participates in a feedback mechanism with JNK to regulate this apoptotic process and is oppositely regulated by JNK1 and JNK2.Alterations in the extracellular matrix during inflammation, development, or metastatic processes can alter the cellular biology that governs these processes. Under these conditions, an altered matrix can result from proteolytic cleavage or alternative splicing of matrix molecules. In inflammation, proteolysis of extracellular matrix molecules leads to the formation of fragments, such as fibronectin (FN) 1 fragments, that elicit cellular responses different from those elicited by the intact molecule (1-5). For example, disease-associated fragments of FN trigger p53-mediated apoptosis of primary cells, but the intact molecule does not (6 -8). Similarly, alternatively spliced variants of FN elicit different cell responses, and specific domains of FN regulate cell survival (4, 5).Previously we reported that an altered FN matrix triggers apoptosis in primary cells via a novel pathway that is regulated by transcriptionally mediated decreases in p53 and c-Myc levels in primary cells (5). To further decipher this apoptotic pathway, we explored the possible connections between integrin/FAK-mediated signals and the down-regulation of p53. We hypothesized that c-Jun N-terminal kinase (JNK) might be at the crossroads of this signaling pathway, since FAK and associated focal adhesion proteins (Rac1/Pak1/MKK4/JNK) have been linked to p53 status in the apoptosis of primary cells (9, 10). In addition, JNK can phosphorylate (11) and form a complex with p53 to stabilize it (12-16), thereby influencing its activity directly.FAK is an integrin-associated protein tyrosine kinase that is important in integrin signaling. Its activation, triggered by increased phosphorylation of Tyr 397 and other sites, has been implicated in many cellular processes, including cell survival. The N-terminal domain of FAK directs interactions with integrins and growth factor receptors. FAK also has a central catalytic domain, which contains Tyr 397 , a major autophosphorylation site and a site of interaction with the Src homology 2 domain. Its C-terminal noncatalytic domain, also known as FAK-related non-kinase (FRNK), contains sites for multiple protein-protein interactions and a focal adhesion targeting (FA...