Wnt5a/Ror2 mediates temporomandibular joint subchondral bone remodeling.
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.
State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology, School of Stomatology, the Fourth Military Medical University, Xi'an, Shaanxi, China Department of Stomatology, Chinese PLA General Hospital, Beijing, China.
T
T
Yang
State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology, School of Stomatology, the Fourth Military Medical University, Xi'an, Shaanxi, China.
J
J
Zhang
Department of Cardiac Surgery, Air Force General Hospital, PLA, Beijing, China.
Y
Y
Cao
State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology, School of Stomatology, the Fourth Military Medical University, Xi'an, Shaanxi, China.
M
M
Zhang
State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology, School of Stomatology, the Fourth Military Medical University, Xi'an, Shaanxi, China.
L
L
Jing
State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology, School of Stomatology, the Fourth Military Medical University, Xi'an, Shaanxi, China.
K
K
Jiao
State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology, School of Stomatology, the Fourth Military Medical University, Xi'an, Shaanxi, China.
S
S
Yu
Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA.
W
W
Chang
Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA.
D
D
Chen
State Key Laboratory of Military Stomatology, Department of Oral Anatomy and Physiology, School of Stomatology, the Fourth Military Medical University, Xi'an, Shaanxi, China mqwang@fmmu.edu.cn.
M
M
Wang
D000135:Acid Phosphatase / Q000032:analysis; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015519:Bone Density / Q000502:physiology; D016723:Bone Remodeling / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000032:analysis; D018920:Coculture Techniques; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007527:Isoenzymes / Q000032:analysis; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008310:Malocclusion / Q000503:physiopathology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors; D010006:Osteoblasts / Q000502:physiology; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D053245:RANK Ligand / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D000071681:Tartrate-Resistant Acid Phosphatase; D013704:Temporomandibular Joint / Q000502:physiology; D051153:Wnt Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D000071818:Wnt-5a Protein
D000873:Anthracenes; C575935:CXCL12 protein, rat; D054377:Chemokine CXCL12; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C491837:Wnt5a protein, rat; C432165:pyrazolanthrone; D016572:Cyclosporine; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C500913:Ror2 protein, rat; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase
bone marrow stromal cells; bone resorption; mandibular condyle; osteoarthritis; osteoclast; traumatic dental occlusion