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1.
J Dent Res ; 95(3): 292-301, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26534931

ABSTRACT

Heterotopic cartilage develops in certain pathologic conditions, including those affecting the human temporomandibular joint (TMJ), but the underlying molecular mechanisms remain obscure. This is in part due to the fact that a reliable animal model of such TMJ diseases is not available. Here, we show that aberrant chondrocyte differentiation and ectopic cartilage formation occur spontaneously in proteoglycan 4 (Prg4) mutant TMJ discs without further invasive procedure. By 2 mo of age, mutant disc cells displayed chondrocyte transdifferentiation, accompanied by strong expression of cartilage master gene Sox9 and matrix genes aggrecan and type II collagen. By 6 mo, heterotopic cartilage had formed in the discs and expressed cartilage hypertrophic markers Runx2 and ColX. The ectopic tissue grew in size over time and exhibited regional mineralization by 12 mo. Bone morphogenetic protein (BMP) signaling was activated with the ectopic chondrogenic cells and chondrocytes, as indicated by phosphorylated Smad 1/5/8 nuclear staining and by elevated expression of Bmp2, Bmpr1b, Bmpr2, and BMP signaling target genes. Likewise, we found that upon treatment with recombinant human BMP 2 in high-density micromass culture, mutant disc cells differentiated into chondrocytes and synthesized cartilage matrix more robustly than control cells. Importantly, a specific kinase inhibitor of BMP receptors drastically attenuated chondrogenesis in recombinant human BMP 2-treated mutant disc cultures. Unexpectedly, we found that Prg4 was expressed at joint-associated sites, including disc/muscle insertion and muscle/bone interface, and all these structures were abnormal in Prg4 mutants. Our data indicate that Prg4 is needed for TMJ disc integrity and function and that its absence leads to ectopic chondrogenesis and cartilage formation in conjunction with abnormal BMP signaling. Our findings imply that the BMP signaling pathway could be a potential therapeutic target for prevention or inhibition of ectopic cartilage formation in TMJ disease.


Subject(s)
Bone Morphogenetic Proteins/physiology , Chondrogenesis/physiology , Choristoma/physiopathology , Proteoglycans/genetics , Signal Transduction/physiology , Temporomandibular Joint Disc/physiopathology , Aggrecans/analysis , Animals , Bone Morphogenetic Protein 2/pharmacology , Bone Morphogenetic Protein Receptors, Type I , Bone Morphogenetic Protein Receptors, Type II/analysis , Calcification, Physiologic/physiology , Cell Differentiation/genetics , Cell Transdifferentiation/genetics , Chondrocytes/physiology , Collagen Type II/analysis , Collagen Type X/analysis , Core Binding Factor Alpha 1 Subunit/analysis , Mice , Mutation/genetics , Proteoglycans/analysis , Recombinant Proteins/pharmacology , SOX9 Transcription Factor/analysis , Smad1 Protein/analysis , Smad5 Protein/analysis , Smad8 Protein/analysis , Tissue Culture Techniques , Transforming Growth Factor beta/pharmacology
2.
J Dent Res ; 93(7): 663-70, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24834922

ABSTRACT

The Proteoglycan 4 (Prg4) product lubricin plays essential roles in boundary lubrication and movement in limb synovial joints, but its roles in temporomandibular joint (TMJ) are unclear. Thus, we characterized the TMJ phenotype in wild-type and Prg4(-/-) mouse littermates over age. As early as 2 weeks of age, mutant mice exhibited hyperplasia in the glenoid fossa articular cartilage, articular disc, and synovial membrane. By 1 month of age, there were fewer condylar superficial tenascin-C/Col1-positive cells and more numerous apoptotic condylar apical cells, while chondroprogenitors displayed higher mitotic activity, and Sox9-, Col2-, and ColX-expressing chondrocyte zones were significantly expanded. Mutant subchondral bone contained numerous Catepsin K-expressing osteoclasts at the chondro-osseous junction, increased invasive marrow cavities, and suboptimal subchondral bone. Mutant glenoid fossa, disc, synovial cells, and condyles displayed higher Hyaluronan synthase 2 expression. Mutant discs also lost their characteristic concave shape, exhibited ectopic chondrocyte differentiation, and occasionally adhered to condylar surfaces. A fibrinoid substance of unclear origin often covered the condylar surface. By 6 months of age, mutant condyles displayed osteoarthritic degradation with apical/mid-zone separation. In sum, lubricin exerts multiple essential direct and indirect roles to preserve TMJ structural and cellular integrity over post-natal life.


Subject(s)
Proteoglycans/physiology , Temporomandibular Joint/anatomy & histology , Age Factors , Animals , Apoptosis/physiology , Bone Marrow/pathology , Cartilage, Articular/pathology , Cathepsin K/analysis , Cell Differentiation/physiology , Chondrocytes/pathology , Collagen Type I/analysis , Collagen Type II/analysis , Collagen Type X/analysis , Glucuronosyltransferase/analysis , Hyaluronan Synthases , Hyperplasia , Mandibular Condyle/pathology , Mice , Mice, Mutant Strains , Osteoarthritis/pathology , Osteoclasts/pathology , SOX9 Transcription Factor/analysis , Synovial Membrane/pathology , Temporal Bone/pathology , Temporomandibular Joint/physiology , Temporomandibular Joint Disc/pathology , Temporomandibular Joint Disorders/pathology , Tenascin/analysis
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