David A Reed1, Yan Zhao2, Michael Han3, Louis G Mercuri4, Michael Miloro5. 1. Assistant Professor, Department of Oral Biology, University of Illinois at Chicago, Chicago, IL. Electronic address: reedd@uic.edu. 2. Research Associate, Department of Oral Biology, University of Illinois at Chicago, Chicago, IL. 3. Assistant Professor, Department of Oral and Maxillofacial Surgery, University of Illinois at Chicago, Chicago, IL. 4. Visiting Professor, Department of Orthopaedic Surgery, Rush University, Chicago, IL; Adjunct Professor, Department of Bioengineering, University of Illinois at Chicago, Chicago, IL. 5. Adjunct Professor, Department of Bioengineering, University of Illinois at Chicago, Chicago, IL; Professor and Head, Department of Oral and Maxillofacial Surgery, University of Illinois at Chicago, Chicago, IL.
Abstract
PURPOSE: Mechanical overloading is a key initiating condition for temporomandibular joint (TMJ) osteoarthritis (OA). The integrin-focal adhesion kinase (FAK) signaling axis is implicated in the mechanobiological response of cells through phosphorylation at Tyr397 (pFAK) but poorly defined in TMJ health and disease. We hypothesize that mechanical overloading disrupts TMJ homeostasis through dysregulation of FAK signaling. MATERIALS AND METHODS: To assess if FAK and pFAK are viable clinical targets for TMJ OA, peri-articular tissues were collected from patients with TMJ OA receiving a total TMJ replacement. To compare clinical samples with preclinical in vivo studies of TMJ OA, the joints of c57/bl6 mice were surgically destabilized and treated with and without inhibitor of pFAK (iFAK). FAK signaling and TMJ OA progression was evaluated and compared using RT-PCR, western blot, immunohistochemistry, and histomorphometry. To evaluate mechanical overloading in vitro, primary murine mandibular fibrochondrocytes were seeded in a 4% agarose-collagen scaffold and loaded in a compression bioreactor with and without iFAK. RESULTS: FAK/pFAK was mostly absent from the articular cartilage layer in the clinical sample and suppressed on the central condyle and elevated on the lateral and medial condyle in murine TMJ OA. In vitro, compressive loading lowered FAK/pFAK levels and elevated the expression of TGFβ, NG2, and MMP-13. iFAK treatment suppressed MMP13 and Col6 and elevated TGFβ, NG2, and ACAN in a load independent manner. In vivo, iFAK treatment moderately attenuated OA progression and increased collagen maturation. CONCLUSION: These data illustrate that FAK/pFAK is implicated in the signaled dysfunction of excessive mechanical loading during TMJ OA and that iFAK treatment can moderately attenuate the progression of cartilage degeneration in the mandibular condyle.
PURPOSE: Mechanical overloading is a key initiating condition for temporomandibular joint (TMJ) osteoarthritis (OA). The integrin-focal adhesion kinase (FAK) signaling axis is implicated in the mechanobiological response of cells through phosphorylation at Tyr397 (pFAK) but poorly defined in TMJ health and disease. We hypothesize that mechanical overloading disrupts TMJ homeostasis through dysregulation of FAK signaling. MATERIALS AND METHODS: To assess if FAK and pFAK are viable clinical targets for TMJ OA, peri-articular tissues were collected from patients with TMJ OA receiving a total TMJ replacement. To compare clinical samples with preclinical in vivo studies of TMJ OA, the joints of c57/bl6 mice were surgically destabilized and treated with and without inhibitor of pFAK (iFAK). FAK signaling and TMJ OA progression was evaluated and compared using RT-PCR, western blot, immunohistochemistry, and histomorphometry. To evaluate mechanical overloading in vitro, primary murine mandibular fibrochondrocytes were seeded in a 4% agarose-collagen scaffold and loaded in a compression bioreactor with and without iFAK. RESULTS: FAK/pFAK was mostly absent from the articular cartilage layer in the clinical sample and suppressed on the central condyle and elevated on the lateral and medial condyle in murine TMJ OA. In vitro, compressive loading lowered FAK/pFAK levels and elevated the expression of TGFβ, NG2, and MMP-13. iFAK treatment suppressed MMP13 and Col6 and elevated TGFβ, NG2, and ACAN in a load independent manner. In vivo, iFAK treatment moderately attenuated OA progression and increased collagen maturation. CONCLUSION: These data illustrate that FAK/pFAK is implicated in the signaled dysfunction of excessive mechanical loading during TMJ OA and that iFAK treatment can moderately attenuate the progression of cartilage degeneration in the mandibular condyle.
Authors: Jihye Seong; Arash Tajik; Jie Sun; Jun-Lin Guan; Martin J Humphries; Susan E Craig; Asha Shekaran; Andrés J García; Shaoying Lu; Michael Z Lin; Ning Wang; Yingxiao Wang Journal: Proc Natl Acad Sci U S A Date: 2013-11-12 Impact factor: 11.205