TMJ Degeneration in SAMP8 Mice is Accompanied by Deranged Ihh Signaling

Ishizuka, Yoichi; Shibukawa, Yoshihiro; Nagayama, Motohiko; Decker, Rebekah S.; Kinumatsu, Takashi; Saito, Akiko; Pacifici, Maurizio; Koyama, Eiki

doi:10.1177/0022034513519649

Cited by 25 publications

(22 citation statements)

References 33 publications

(36 reference statements)

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“…OA changes and maladaptive remodeling can occur in the TMJ when mechanical stresses exceed its biomechanical adaptive capacity (Ishizuka et al, 2014; Tanaka et al, 2008a), but little is known as to whether the various TMJ components respond to such pathological insults in unison or differentially, thus limiting current understanding of TMJ pathogenesis. To this end, we further characterized the OA-like structural and phenotypic changes occurring in articular cartilage and discs in Prg4 -null mice at different post-natal ages.…”

Section: Resultsmentioning

confidence: 99%

Osteophyte formation and matrix mineralization in a TMJ osteoarthritis mouse model are associated with ectopic hedgehog signaling

et al. 2016

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The temporomandibular joint (TMJ) is a diarthrodial joint that relies on lubricants for frictionless movement and long-term function. It remains unclear what temporal and causal relationships may exist between compromised lubrication and onset and progression of TMJ disease. Here we report that Proteoglycan 4 (Prg4)-null TMJs exhibit irreversible osteoarthritis-like changes over time and are linked to formation of ectopic mineralized tissues and osteophytes in articular disc, mandibular condyle and glenoid fossa. In the presumptive layer of mutant glenoid fossa’s articulating surface, numerous chondrogenic cells and/or chondrocytes emerged ectopically within the type I collagen-expressing cell population, underwent endochondral bone formation accompanied by enhanced Ihh expression, became entrapped into temporal bone mineralized matrix, and thereby elicited excessive chondroid bone formation. As the osteophytes grew, the roof of the glenoid fossa/eminence became significantly thicker and flatter, resulting in loss of its characteristic concave shape for accommodation of condyle and disc. Concurrently, the condyles became flatter and larger and exhibited ectopic bone along their neck, likely supporting the enlarged condylar heads. Articular discs lost their concave configuration, and ectopic cartilage developed and articulated with osteophytes. In glenoid fossa cells in culture, hedgehog signaling stimulated chondrocyte maturation and mineralization including alkaline phosphatase, while treatment with hedgehog inhibitor HhAntag prevented such maturation process. In sum, our data indicate that Prg4 is needed for TMJ integrity and long-term postnatal function. In its absence, progenitor cells near presumptive articular layer and disc undergo ectopic chondrogenesis and generate ectopic cartilage, possibly driven by aberrant activation of Hh signaling. The data suggest also that the Prg4-null mice represent a useful model to study TMJ osteoarthritis-like degeneration and clarify its pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Osteophyte formation and matrix mineralization in a TMJ osteoarthritis mouse model are associated with ectopic hedgehog signaling

et al. 2016

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“…Several studies explored the molecular mechanisms and signal pathways of mechanical stress-induced TMJOA. Malocclusion-accelerated early abnormal condylar organization in the senescence-accelerated mice is accompanied by a downregulation of Indian hedgehog signaling (Ishizuka et al 2014). This finding suggests that a possible therapeutic effect of early restoration of hedgehog signaling or that inhibition of endoplasmic reticulum stress can minimize or even prevent the excessive mechanical stress-induced degeneration of TMJs.…”

Section: Excessive Mechanical Stressmentioning

confidence: 99%

Current Understanding of Pathogenesis and Treatment of TMJ Osteoarthritis

et al. 2015

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Osteoarthritis is a common disease that can cause severe pain and dysfunction in any joint, including the temporomandibular joint (TMJ). TMJ osteoarthritis (TMJOA) is an important subtype in the classification of temporomandibular disorders. TMJOA pathology is characterized by progressive cartilage degradation, subchondral bone remodeling, and chronic inflammation in the synovial tissue. However, the exact pathogenesis and process of TMJOA remain to be understood. An increasing number of studies have recently focused on inflammation and remodeling of subchondral bone during the early stage of TMJOA, which may elucidate the possible mechanism of initiation and progression of TMJOA. The treatment strategy for TMJOA aims at relieving pain, preventing the progression of cartilage and subchondral bone destruction, and restoring joint function. Conservative therapy with nonsteroidal anti-inflammatory drugs, splint, and physical therapy, such as low-energy laser and arthrocentesis, are the most common treatments for TMJOA. These therapies are effective in most cases in relieving the signs and symptoms, but their long-term therapeutic effect on the pathologic articular structure is unsatisfactory. A treatment that can reverse the damage of TMJOA remains unavailable to date. Treatments that prevent the progression of cartilage degradation and subchondral bone damage should be explored, and regeneration for the TMJ may provide the ideal long-term solution. This review summarizes the current understanding of mechanisms underlying the pathogenesis and treatment of TMJOA.

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“…The apical layer in developing and adult condyles contains superficial cells producing Proteoglycan 4 (Prg4) and polymorphic cells that display stem cell-like characteristics [64]. Polymorphic cells give rise to chondrocytes for condylar growth and play a role in homeostasis and/or remodeling of condylar cartilage in response to mechanical stress [65,66]. Condylar cartilage length along its longitudinal axis in mice was ca.…”

Section: Cellular Organization Of Condylar Cartilage In Postnatal Stagesmentioning

confidence: 99%

“…It is likely that decreased Hh signaling is associated with age-related TMJ degenerative changes [66,71]. In senescence-accelerated-prone 8 (SAMP8) mice, which develop early osteoarthritis-like changes in synovial joints at a high frequency [72], condylar cartilage in young SAMP8 mice displayed early-onset degenerative changes, concomitant with reductions in superficial/chondro-progenitor cells, proteoglycan/collagen content, and Ihh-expressing chondrocytes [66]. These data clearly demonstrate that Ihh signaling is essential for condylar superficial/progenitor cell layer development and function in postnatal condylar cartilage of TMJs, and its ablation and/or decreased expression in juvenile mice leads to degenerative changes in TMJ condyles, manifesting abnormal chondrocyte maturation and subchondral bone formation in the condyle.…”

Section: Effect Of Conditional Ihh Signaling Ablation In Postnatal Stmentioning

confidence: 99%

“…By 5 months old, μCT analysis revealed that mutant subchondral bone became porous ( Figure 5E), leading to decreased bone volume fraction and increased trabecular spacing compared to age-matched controls ( Figure 5C). It is likely that decreased Hh signaling is associated with age-related TMJ degenerative changes [66,71]. In senescence-accelerated-prone 8 (SAMP8) mice, which develop early osteoarthritis-like changes in synovial joints at a high frequency [72], condylar cartilage in young SAMP8 mice displayed early-onset degenerative changes, concomitant with reductions in superficial/chondro-progenitor cells, proteoglycan/collagen content, and Ihh-expressing chondrocytes [66].…”

Section: Effect Of Conditional Ihh Signaling Ablation In Postnatal Stmentioning

confidence: 99%

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The Roles of Indian Hedgehog Signaling in TMJ Formation

Bechtold

Kurio

Nah

et al. 2019

IJMS

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The temporomandibular joint (TMJ) is an intricate structure composed of the mandibular condyle, articular disc, and glenoid fossa in the temporal bone. Apical condylar cartilage is classified as a secondary cartilage, is fibrocartilaginous in nature, and is structurally distinct from growth plate and articular cartilage in long bones. Condylar cartilage is organized in distinct cellular layers that include a superficial layer that produces lubricants, a polymorphic/progenitor layer that contains stem/progenitor cells, and underlying layers of flattened and hypertrophic chondrocytes. Uniquely, progenitor cells reside near the articular surface, proliferate, undergo chondrogenesis, and mature into hypertrophic chondrocytes. During the past decades, there has been a growing interest in the molecular mechanisms by which the TMJ develops and acquires its unique structural and functional features. Indian hedgehog (Ihh), which regulates skeletal development including synovial joint formation, also plays pivotal roles in TMJ development and postnatal maintenance. This review provides a description of the many important recent advances in Hedgehog (Hh) signaling in TMJ biology. These include studies that used conventional approaches and those that analyzed the phenotype of tissue-specific mouse mutants lacking Ihh or associated molecules. The recent advances in understanding the molecular mechanism regulating TMJ development are impressive and these findings will have major implications for future translational medicine tools to repair and regenerate TMJ congenital anomalies and acquired diseases, such as degenerative damage in TMJ osteoarthritic conditions.

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TMJ Degeneration in SAMP8 Mice is Accompanied by Deranged Ihh Signaling

Cited by 25 publications

References 33 publications

Osteophyte formation and matrix mineralization in a TMJ osteoarthritis mouse model are associated with ectopic hedgehog signaling

Osteophyte formation and matrix mineralization in a TMJ osteoarthritis mouse model are associated with ectopic hedgehog signaling

Current Understanding of Pathogenesis and Treatment of TMJ Osteoarthritis

The Roles of Indian Hedgehog Signaling in TMJ Formation

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