Fibroblast growth factor-2 stimulates directed migration of periodontal ligament cells via PI3K/AKT signaling and CD44/hyaluronan interaction.

Fibroblast growth factor-2 (FGF-2) regulates a variety of functions of the periodontal ligament (PDL) cell, which is a key player during tissue regeneration following periodontal tissue breakdown by periodontal disease. In this study, we investigated the effects of FGF-2 on the cell migration and related signaling pathways of MPDL22, a mouse PDL cell clone. FGF-2 activated the migration of MPDL22 cells and phosphorylation of phosphatidylinositol 3-kinase (PI3K) and akt. The P13K inhibitors, Wortmannin and LY294002, suppressed both cell migration and akt activation in MPDL22, suggesting that the PI3K/akt pathway is involved in FGF-2-stimulated migration of MPDL22 cells. Moreover, in response to FGF-2, MPDL22 showed increased CD44 expression, avidity to hyaluronan (HA) partly via CD44, HA production and mRNA expression of HA synthase (Has)-1, 2, and 3. However, the distribution of HA molecular mass produced by MPDL22 was not altered by FGF-2 stimulation. Treatment of transwell membrane with HA facilitated the migration of MPDL22 cells and an anti-CD44 neutralizing antibody inhibited it. Interestingly, the expression of CD44 was colocalized with HA on the migrating cells when stimulated with FGF-2. Furthermore, an anti-CD44 antibody and small interfering RNA for CD44 significantly decreased the FGF-2-induced migration of MPDL22 cells. Taken together, PI3K/akt and CD44/HA signaling pathways are responsible for FGF-2-mediated cell motility of PDL cells, suggesting that FGF-2 accelerates periodontal regeneration by regulating the cellular functions including migration, proliferation and modulation of extracellular matrix production.

Shimabukuro Y ，Terashima H ，Takedachi M ，Maeda K ，Nakamura T ，Sawada K ，Kobashi M ，Awata T ，Oohara H ，Kawahara T ，Iwayama T ，Hashikawa T ，Yanagita M ，Yamada S ，Murakami S ... -  《-》

Hyaluronan-CD44 interaction stimulates Rac1 signaling and PKN gamma kinase activation leading to cytoskeleton function and cell migration in astrocytes.

Bourguignon LY ，Gilad E ，Peyrollier K ，Brightman A ，Swanson RA ... -  《JOURNAL OF NEUROCHEMISTRY》

The role of the hyaluronan receptor CD44 in mesenchymal stem cell migration in the extracellular matrix.

Zhu H ，Mitsuhashi N ，Klein A ，Barsky LW ，Weinberg K ，Barr ML ，Demetriou A ，Wu GD ... -  《STEM CELLS》

Fibroblast growth factor-2 regulates the synthesis of hyaluronan by human periodontal ligament cells.

Basic fibroblast growth factor (FGF-2) can enhance biological potentials of periodontal ligament cells and its topical application induces considerable periodontal tissue regeneration in vivo. In this study, we examined the effect of FGF-2 on the production of hyaluronan (HA), an extracellular matrix playing important roles in homeostasis and inflammatory/wound healing responses, by human periodontal ligament (HPDL) cells. An inhibition binding-protein assay revealed that FGF-2 significantly increased HA production by HPDL cells in a dose dependent manner. Analysis by HPLC revealed that in conditioned medium of FGF-2-treated HPDL cells HA had a higher molecular mass, compared to that of untreated HPDL cells. RT-PCR analysis revealed the enhancement of mRNA expression of hyaluronan synthase (HAS) 1 and HAS 2, both of which contribute to the production of HA with a high molecular mass, but not HAS 3 in the FGF-2-treated HPDL cells. In contrast, three isoforms of hyaluronidase (HYAL) transcript were unchanged in the FGF-2-treated HPDL cells. These results provide new evidence for the possible involvement of FGF-2 in the regulation of HA production and its appreciable roles in not only homeostasis but also regeneration of periodontal tissues.

Shimabukuro Y ，Ichikawa T ，Takayama S ，Yamada S ，Takedachi M ，Terakura M ，Hashikawa T ，Murakami S ... -  《JOURNAL OF CELLULAR PHYSIOLOGY》

Fibroblast growth factor-2 regulates expression of osteopontin in periodontal ligament cells.

Terashima Y ，Shimabukuro Y ，Terashima H ，Ozasa M ，Terakura M ，Ikezawa K ，Hashikawa T ，Takedachi M ，Oohara H ，Yamada S ，Murakami S ... -  《-》