BIO alleviated compressive mechanical force‐mediated mandibular cartilage pathological changes through Wnt/β‐catenin signaling activation

Abstract

Osteoarthritis induced by compressive mechanical force is characterized by decreased chondrocyte proliferation and degradation of the ECM. To examine underlying mechanisms of the pathological changes of mandibular cartilage induced by compressive mechanical force, an established animal model was used to examine Wnt signaling activation by glycogen synthase kinase-3 beta (GSK3β) inhibitor 6-Bromoindirubin-3'-oxime (BIO) injection in vivo. Histological changes in mandibular cartilage were assessed via hematoxylin & eosin (HE), masson, and alcian blue staining. Immunohistochemistry and real-time PCR were performed to evaluate activation of the Wnt signaling pathway and chondrocytes proliferation markers. Chondrocytes apoptosis was examined by TUNEL staining. During the compressive mechanical force loading-mediated process, Wnt signaling was largely inhibited, which showed the inhibited expression of β-catenin and the increased expression of GSK-3β. The expression of chondrocytes proliferation markers Ki67, and proliferating cell nuclear antigen (PCNA) also decreased. With BIO injection, the Wnt signaling was restored and the proliferation of mandibular chondrocytes was also increased in the late stage (7 days) of compressive mechanical force loading. Finally, the decreasing mandibular cartilage thickness, the degradation of extracellular matrix, and the erosion of bone trabecula were subsequently restored. Also, the changes of extracellular matrix markers such as collagen II and collagen X, matrix metalloproteases, and inflammatory cytokines were reversed followed by the injection of BIO. In summary, compressive mechanical force decreased endogenously Wnt signaling, leading to impaired proliferation in chondrocytes and degradation in cartilage matrix. Restoration of Wnt signaling largely recovered the proliferation defects and alleviated the pathological changes of mandibular cartilage. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1228-1237, 2018.

Pathological mechanism of chondrocytes and the surrounding environment during osteoarthritis of temporomandibular joint

“…These pathological changes can be recovered by restoring the β-catenin signalling. 54 However, other authors found that mice with conditional F I G U R E 2 Pathways associated with chondrocyte death in TMJ osteoarthritis. Apoptosis and necroptosis are promoted in TMJ osteoarthritis, but the general trend of autophagy activity is inhibited β-catenin activation showed TMJ osteoarthritis-like phenotypes and up-regulation of MMP13 and ADAMT5 expression.…”

“…Compressive mechanical force reduces endogenous β‐catenin and leads to ECM degradation. These pathological changes can be recovered by restoring the β‐catenin signalling 54 . However, other authors found that mice with conditional β‐catenin activation showed TMJ osteoarthritis‐like phenotypes and up‐regulation of MMP13 and ADAMT5 expression 21,55 …”

Molecular mechanisms of mechanical load-induced osteoarthritis

“…A study by Yuan reported that Wnt pathway inhibition by overload is characterized by OA manifestations such as induced ECM degradation, upregulated inflammatory factors, and trabecular bone erosion. The activation of the Wnt pathway can reverse these symptoms [38]. Physiological stress can activate Wnt signaling to inhibit osteoclast production and promote COL2A1 synthesis [39].…”

Rapid Osteogenic Enhancement of Stem Cells in Human Bone Marrow Using a Glycogen-Synthease-Kinase-3-Beta Inhibitor Improves Osteogenic Efficacy In Vitro and In Vivo

“…Interestingly, cWnt signaling has been recently shown to drive macrophages to the M2 subtype , and bioactive factors secreted by M2 macrophages have osteogenic effects on osteoprogenitors . In a recent study, BIO has also been shown to stimulate the proliferation of mandibular chondrocytes in vivo .…”