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.
The synovial cavity and its fluid are essential for joint function and lubrication, but their developmental biology remains largely obscure. Here, we analyzed E12.5-E18.5 mouse embryo hindlimbs and ...discovered that cavitation initiates around E15.0 with emergence of multiple, discrete, m-wide tissue discontinuities we term microcavities in interzone, evolving into a single joint-wide cavity within 12 hrs in knees and within 72-84 hrs in interphalangeal joints. The microcavities were circumscribed by cells as revealed by mTmG imaging and exhibited a carbohydrate and protein content based on infrared spectral imaging at micro and nanoscale. Accounting for differing cavitation kinetics, we found that the growing femur and tibia anlagen progressively flexed at the knee over time, with peak angulation around E15.5 exactly when the full knee cavity consolidated; however, interphalangeal joint geometry changed minimally over time. Indeed, cavitating knee interzone cells were elongated along the flexion angle axis and displayed oblong nuclei, but these traits were marginal in interphalangeal cells. Conditional Gdf5Cre-driven ablation of Has2 -responsible for production of the joint polysaccharide lubricant hyaluronic acid (HA)- delayed the cavitation process. Our data reveal that cavitation is a stepwise process brought about by sequential action of microcavities, skeletal flexion and elongation, and HA accumulation.
Condylar articular cartilage in mouse temporomandibular joint develops from progenitor cells near the articulating surface that proliferate, undergo chondrogenesis and mature into hypertrophic ...chondrocytes. However, it remains unclear how these processes are regulated, particularly postnatally. Here we focused on the apical polymorphic layer rich in progenitors and asked whether the phenotype and fate of the cells require signaling by Indian hedgehog (Ihh) previously studied in developing long bones. In condyles in newborn mice, the apical polymorphic/progenitor cell layer was ~10 cell layer-thick and expressed the articular matrix marker Tenascin-C (Tn-C), and the underlying thick cell layer expressed Tn-C as well as the chondrogenic master regulator Sox9. By 1 month, condylar cartilage had gained its full width, but became thinner along its main longitudinal axis and displayed hypertrophic chondrocytes. By 3 months, articular cartilage consisted of a 2–3 cell layer-thick zone of superficial cells and chondroprogenitors expressing both Tn-C and Sox9 and a bottom zone of chondrocytes displaying vertical matrix septa. EdU cell tracing in juvenile mice revealed that conversion of chondroprogenitors into chondrocytes and hypertrophic chondrocytes required about 48 and 72 h, respectively. Notably, EdU injection in 3 month-old mice labeled both progenitors and maturing chondrocytes by 96 h. Conditional ablation of Ihh in juvenile/early adult mice compromised chondroprogenitor organization and function and led to reduced chondroprogenitor and chondrocyte proliferation. The phenotype of mutant condyles worsened over time as indicated by apoptotic chondrocyte incidence, ectopic chondrocyte hypertrophy, chondrocyte column derangement and subchondral bone deterioration. In micromass cultures of condylar apical cells, hedgehog (Hh) treatment stimulated chondrogenesis and alkaline phosphatase (APase) activity, while treatment with HhAntag inhibited both. Our findings indicate that the chondroprogenitor layer is continuously engaged in condylar growth postnatally and its organization and functioning depend on hedgehog signaling.
•Development of progentor layer and structure of condylar articular cartilage are clarified during postnatal TMJ development.•Chondroprogenitors and their fate are clarified in postnatal condylar articular cartilage.•We evaluate gene recombination in postnatal TMJs using Aggrecan (Agc)-CreER;R26-tdTomato reporter mice.•The role of Ihh signaling is clarified in postnatal TMJs using compound Agc-CreER;Ihh f/f;Gli1-nLacZ mice.•Ablation of Ihh signaling in postnatal Agc-CreER;Ihh f/f mice disrupts chondroprogenitor function.•Hh signaling promotes chondrogenesis and chondrocyte maturation in condylar apical cell culture.
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.
•Prg4-null TMJs exhibit irreversible osteoarthritis-like changes.•Osteophyte formation in Prg4-null TMJs is associated with ectopic hedgehog signaling.•Loss of Prg4 function results in abnormal endochondral bone formation in the glenoid fossa.•Prg4-mediated boundary lubrication is indispensable for TMJ maintenance.
Osteochondromas and enchondromas are the most common tumors affecting the skeleton. Osteochondromas can occur as multiple lesions, such as those in patients with hereditary multiple exostoses. ...Unexpectedly, while studying the role of β-catenin in cartilage development, we found that its conditional deletion induces ectopic chondroma-like cartilage formation in mice. Postnatal ablation of β-catenin in cartilage induced lateral outgrowth of the growth plate within 2 weeks after ablation. The chondroma-like masses were present in the flanking periosteum by 5 weeks and persisted for more than 6 months after β-catenin ablation. These long-lasting ectopic masses rarely contained apoptotic cells. In good correlation, transplants of β-catenin-deficient chondrocytes into athymic mice persisted for a longer period of time and resisted replacement by bone compared to control wild-type chondrocytes. In contrast, a β-catenin signaling stimulator increased cell death in control chondrocytes. Immunohistochemical analysis revealed that the amount of detectable β-catenin in cartilage cells of osteochondromas obtained from hereditary multiple exostoses patients was much lower than that in hypertrophic chondrocytes in normal human growth plates. The findings in our study indicate that loss of β-catenin expression in chondrocytes induces periosteal chondroma-like masses and may be linked to, and cause, the persistence of cartilage caps in osteochondromas.
Fibromyalgia has recently emerged as a diagnosis of exclusion for patients with chronic, widespread pain. We investigated the influence of this comorbidity on outcomes of total knee arthroplasty ...(TKA). We matched 59 patients (90 knees) who underwent primary TKA with a diagnosis of fibromyalgia to control patients who underwent the same surgery. Postoperative satisfaction and functional outcomes were assessed using a Likert scale and the SF-36 survey, respectively. At 3.4 years' follow-up, fibromyalgia patients were less satisfied with TKA than control patients, and had lower preoperative and postoperative SF-36 scores. They demonstrated improvement comparable to that of controls following TKA, however. Fibromyalgia patients appear to show improvement comparable to that of controls following surgery. This syndrome should not be considered a contraindication for surgery.
Objective
The network theory of psychopathology examines networks of interconnections across symptoms. Several network studies of disordered eating have identified central and bridge symptoms in ...Western samples, yet network models of disordered eating have not been tested in non‐Western samples. The current study tested a network model of disordered eating in Iranian adolescents and college students, as well as models of co‐occurring depression and self‐esteem.
Method
Participants were Iranian college students (n= 637) and adolescents (n = 1,111) who completed the Eating Disorder Examination‐Questionnaire (EDE‐Q), Rosenberg Self‐Esteem Scale (RSES) and Beck Depression Inventory, Second Edition (BDI‐II). We computed six Glasso networks and identified central and bridge symptoms.
Results
Central disordered eating nodes in most models were a desire to lose weight and discomfort when seeing one's own body. Central self‐esteem and depression nodes were feeling useless and self‐dislike, respectively. Feeling like a failure was the most common bridge symptom between disordered eating and depression symptoms. With exception of a few differences in some edges, networks did not significantly differ in structure.
Discussion
Desire to lose weight was the most central node in the networks, which is consistent with sociocultural theories of disordered eating development, as well as prior network models from Western‐culture samples. Feeling like a failure was the most central bridge symptom between depression and disordered eating, suggesting that very low self‐esteem may be a shared correlate or risk factor for disordered eating and depression in Iranian adolescents and young adults.
Black women living with HIV (BWLWH) in the U.S. face microaggressions based on race, gender, HIV-status, and sexual orientation. We examined changes in daily microaggressions and related distress ...among 143 BWLWH in Miami, FL. Microaggression-related distress increased from 52% at baseline/October, peaked at 70% during the holidays (November/December), declined to 55% in March when COVID-19 social distancing began, and peaked to 83% in June/July 2020 during widespread Black Lives Matters protests. Baseline viral suppression was associated with lower microaggressions across the 9-months. Microaggression-related distress may change due to social context and research is needed on microaggressions and viral load overtime.
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