Wnt5a/Ror2 Mediates Temporomandibular Joint Subchondral Bone Remodeling

Abstract

Increased subchondral trabecular bone turnover due to imbalanced bone-resorbing and bone-forming activities is a hallmark of osteoarthritis (OA). Wnt5a/Ror2 signaling, which can derive from bone marrow stromal cells (BMSCs), takes a role in modulating osteoblast and osteoclast formation. We showed previously that experimentally unilateral anterior crossbites (UACs) elicited OA-like lesions in mice temporomandibular joints (TMJs), displaying as subchondral trabecular bone loss. Herein, we tested the role of BMSC-derived Wnt5a/Ror2 signaling in regulating osteoclast precursor migration and differentiation in this process. The data confirmed the decreased bone mass, increased tartrate-resistant acid phosphatase (TRAP)-positive cell number, and enhanced osteoclast activity in TMJ subchondral trabecular bone of UAC-treated rats. Interestingly, the osteoblast activity in the tissue of TMJ subchondral trabecular bone of these UAC-treated rats was also enhanced, displaying as upregulated expressions of osteoblast markers and increased proliferation, migration, and differentiation capabilities of the locally isolated BMSCs. These BMSCs showed an increased CXCL12 protein expression level and upregulated messenger RNA expressions of Rankl, Wnt5a, and Ror2. Ex vivo data showed that their capacities of inducing migration and differentiation of osteoclast precursors were enhanced, and these enhanced capabilities were restrained after blocking their Ror2 signaling using small interfering RNA (siRNA) assays. Reducing Ror2 expression in the BMSC cell line by siRNA or blocking the downstream signalings with specific inhibitors also demonstrated a suppression of the capacity of the BMSC cell line to promote Wnt5a-dependent migration (including SP600125 and cyclosporine A) and differentiation (cyclosporine A only) of osteoclast precursors. These findings support the idea that Wnt5a/Ror2 signaling in TMJ subchondral BMSCs enhanced by UAC promoted BMSCs to increase Cxcl12 and Rankl expression, in which JNK and/or Ca(2+)/NFAT pathways were involved and therefore were engaged in enhancing the migration and differentiation of osteoclast precursors, leading to increased osteoclast activity and an overall TMJ subchondral trabecular bone loss in the UAC-treated rats.

Molecular changes in peripheral blood involving osteoarthritic joint remodelling

“…Based on a gene array analysis, Appleton et al indicated that the gene expression changes in a surgically developed rat OA model were similar to those found in human OA . Recently, we developed a prosthetic unilateral anterior crossbite (UAC) rodent model in which typical OA‐like lesions were observed in TMJs, such as chondrocyte death, cartilage matrix loss, osteochondral interface stiffening and abnormal reparative bone turnover . In the present study, we first detected molecular changes in the PBLs of UAC rats.…”

“…13 Recently, we developed a prosthetic unilateral anterior crossbite (UAC) rodent model in which typical OA-like lesions were observed in TMJs, such as chondrocyte death, cartilage matrix loss, osteochondral interface stiffening and abnormal reparative bone turnover. [14][15][16][17][18] In the present study, we first detected molecular changes in the PBLs of UAC rats. We then described the significance of the molecular changes disclosed in the PBLs of the UAC rats in the related tissues, including the alveolar bone, TMJ disc, mandibular condylar cartilage and subchondral bone.…”

“…UAC was created as previously described by our laboratory. [14][15][16] Briefly, a straight metal tube (ShinvaAnde, Shandong, China) and a curved metal tube (ShinvaAnde, Shandong, China) with an angle of 135° to the labial side at the upper end were bonded with zinc phosphate cement (Shanghai Dental Instrument Factory, Shanghai, China) to the left maxillary and mandibular incisor, respectively, to create an experimental crossbite relationship between the left side incisors. The rats in the control group underwent similar procedures but without bonding of the metal tubes.…”

Wnt/β-catenin Signaling in Osteoarthritis and in Other Forms of Arthritis

“…Wnt5a/Ror2 signaling in bone marrow stromal cells of the subchondral bone was enhanced in a surgically induced TMJ OA mouse model. Cxcl12 and Rankl gene expression induced by JNK and Ca 2+ /NFAT signaling pathways was increased, leading to activation of osteoclast differentiation and enhanced subchondral bone turnover [31]. …”

“…Deletion of Adamts5 or double KO of both Adamts4 and Adamts5 prevented cartilage degradation in a surgically induced knee OA mouse model [55, 56]. In β-catenin overexpressing mice, β - catenin ( ex3 ) Col2CreER , expression of both Adamts4 and Adamts5 genes in disc tissues was upregulated [31]. These findings revealed that Mmp13 and Adamts4 / 5 are critical for cartilage erosion during progression, and pharmacologic inhibition of these enzymes may serve as an alternative strategy for osteoarthritis treatment.…”