Lubricin Protects the Temporomandibular Joint Surfaces from Degeneration

The temporomandibular joint (TMJ) is a specialized synovial joint essential for the mobility and function of the mammalian jaw. The TMJ is composed of the mandibular condyle, the glenoid fossa of the temporal bone, and a fibrocartilagenous disc interposed between these bones. A fibrous capsule, lined on the luminal surface by the synovial membrane, links these bones and retains synovial fluid within the cavity. The major component of synovial fluid is lubricin, a glycoprotein encoded by the gene proteoglycan 4 (Prg4), which is synthesized by chondrocytes at the surface of the articular cartilage and by synovial lining cells. We previously showed that in the knee joint, Prg4 is crucial for maintenance of cartilage surfaces and for regulating proliferation of the intimal cells in the synovium. Consequently, the objective of this study was to determine the role of lubricin in the maintenance of the TMJ. We found that mice lacking lubricin have a normal TMJ at birth, but develop degeneration resembling TMJ osteoarthritis by 2 months, increasing in severity over time. Disease progression in Prg4−/− mice results in synovial hyperplasia, deterioration of cartilage in the condyle, disc and fossa with an increase in chondrocyte number and their redistribution in clusters with loss of superficial zone chondrocytes. All articular surfaces of the joint had a prominent layer of protein deposition. Compared to the knee joint, the osteoarthritis-like phenotype was more severe and manifested earlier in the TMJ. Taken together, the lack of lubricin in the TMJ causes osteoarthritis-like degeneration that affects the articular cartilage as well as the integrity of multiple joint tissues. Our results provide the first molecular evidence of the role of lubricin in the TMJ and suggest that Prg4−/− mice might provide a valuable new animal model for the study of the early events of TMJ osteoarthritis

Atypical CD4(+)/CD8(+) Lymphocytosis and Prolonged Pancytopenia Associated With Human Herpesvirus 6 Reactivation After Autologous Peripheral Blood Stem Cell Transplantation

12 month embargo; published online: 15 March 2019This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Synovial hypertrophy in <i>Prg4</i>⁻^<i>/</i>− mice TMJs.

<p>TMJ sections stained for H&E at 2- and 9-months old mice in control (<i>Prg4</i><b><i>^+/</i></b>⁻) and lubricin null mice <i>(Prg4</i>^{−<b><i>/</i></b>−}). Synovial membranes in the upper joint cavity are indicated by arrows. Control <i>Prg4</i><b><i>^+/</i></b>⁻ mice exhibit a thin synovial lining (A, C, E, and G) compared to the hypertrophied synovium (red bar) observed in <i>Prg4</i>^{−<b><i>/</i></b>−} mice (B, D, F, and H) and characteristic of synovitis. An increase in the severity of synovitis is observed over time, as shown in 2-month-old <i>Prg4</i>^{−<b><i>/</i></b>−} (B, F) versus 9-month-old <i>Prg4</i>^{−<b><i>/</i></b>−} (F, H) mice. Villous digitations (arrowhead), cartilage debris surrounded by synovial membrane (open arrowhead) and detritus rich zones (*) are observed in 9-month-old <i>Prg4</i>^{−<b><i>/</i></b>−} mice. These inflammatory changes were seen primarily in the upper joint cavity, located between the disc (d) and fossa (f). (A–D: 10X, E–H: 20X).</p

Osteoarthritis-like characteristics in TMJ and knee joints in <i>Prg4</i>⁻^<i>/</i>− mice.

<p>(<b>A–D</b>) Representative coronal sections of the TMJ and knee joints of lubricin null (<i>Prg4</i>^{−<b><i>/</i></b>−}) mice at 2- and 9- months of age, stained with H&E. At 2 months, the articular surface of the TMJ condyle displays very few superficial flat chondrocytes, whereas, several superficial zone chondrocytes can still be observed at the cartilage surface in the knee joint. (A and B, arrowheads). In both joints, evidence of lightly stained protein deposition across the entire joint surfaces can be observed (Fig. 4 brackets). At 9 months of age, the cartilage surfaces of both joints display disease progression, chondrocytes are absent from the articular surfaces of both the knee and the TMJ, and the protein layer deposited on all surfaces is enlarged and disrupted (Figs. 4 C and D). In addition, in the TMJ there is a large infiltration of synoviocytes deposited on the surface of the condyle (Fig. 4C *). c: condyle, d: disc, fe: femur, t: tibia.</p

Increased TMJ Osteoarthritis-like characteristics in <i>Prg4</i>⁻^<i>/</i>− mice.

<p>(<b>A–D</b>) Decreased extracellular matrix components in <i>Prg4</i>^{−<b><i>/</i></b>−} mice. Paraffin embedded, formalin fixed TMJ sections at 6-months, histologically stained for Safranin O (SO) (A, B) and immunostained for aggrecan neopeptide (C, D) in <i>Prg4</i><b><i>^+/</i></b>⁻ and <i>Prg4</i>^{−<b>/</b>−} mice. A black dotted line separates the region of columnar chondrocytes in the condyle (below) from the proliferating chondrocytes (above). Note the abundant SO positive staining (red dots) in the proliferating zone in control <i>Prg4</i><b><i>^+/-</i></b> mice and the few positive SO staining in <i>Prg4</i>^{−<b><i>/</i></b>−} null mice. As expected, the opposite is observed for aggrecan neopeptide immuno localization, which shows abundant aggregan neopeptide in proliferating chondrocytes, indicating that in <i>Prg4</i>^{−<b><i>/</i></b>−} mice aggrecan degradation is increased. Insets in C and D correspond to a magnification of the field indicated in the red dotted line and highlight the extracellular localization of aggrecan neopeptide staining (arrows). (<b>E–J</b>) TRAP staining in 2-, 6- and 9- month TMJ sections. Black arrowheads show TRAP+ multinucleated cells (MNC) in resorptive areas of the condyles stained in red (magnified panel on right). (<b>K</b>) Quantitation of TRAP+ MNC at 2-, 6-, and 9- month-old mice showed an increase in osteoclastogenesis of 38.65%, 41.2%, and 45.8% respectively in <i>Prg4</i>^{−<b><i>/</i></b>−}<i>mice</i>, compared to age-matched control mice. Student t-test: *, p<0.05; **, p<0.01. Dotted lines demarcate the surfaces of the condyle and fossa. c: condyle, d: disc, f: fossa.</p

Incidence and risk of xerosis with targeted anticancer therapies

Background Many targeted therapies used in the treatment of cancer can lead to the development of xerosis, but the incidence and relative risk of xerosis have not been ascertained. Objective We conducted a systematic review and metaanalysis of clinical trials, to ascertain the incidence and risk of developing xerosis after taking anticancer drugs. Methods The PubMed (1966-October 2013), Web of Science (January 1998-October 2013), and American Society of Clinical Oncology abstracts (2004-2013) databases were searched for clinical trials of 58 targeted agents. Results were calculated using random or fixed effects models. Results The incidences of all- and high-grade xerosis were 17.9% (95% confidence interval [CI]: 15.6-20.4%) and 1.0% (95% CI: 0.9-1.5%), respectively. The risk of developing all-grade xerosis was 2.99 (95% CI: 2.0-4.3), and it varied across different drugs (P less than .001). Limitations The reporting of xerosis may vary among clinicians and institutions, and the incidence may be affected by age, concomitant medications, comorbidities, and underlying malignancies or skin conditions. Conclusion Patients receiving targeted therapies have a significant risk of developing xerosis. Patients should be counseled and treated early for this symptom to prevent suboptimal dosing and quality of life impairment

Reply to: 'Skin moisturization for xerosis related to targeted anticancer therapies'

To the Editor: We would like to thank Drs Gisondi and Girolomoni for their comments regarding the treatment of xerosis. We agree that salicylic acid and ammonium lactate should be used judiciously, and only on areas of hyperkeratosis without evident dermatitis, as is commonly seen in patients treated with targeted therapies. Indeed, targeted therapies lead to aberrant keratinocyte proliferation, migration, differentiation, and adhesion, all of which result in xerotic skin with retention hyperkeratosis.1 Patients receiving targeted therapies who develop xerosis and hyperkeratosis require rapid resolution of findings, because progression into a grade 3 adverse event dictates interruption, dose decrease, or discontinuation of life-prolonging anticancer treatments. Therefore, according to the treatment algorithm in Fig 4 of our manuscript, salicylic acid or ammonium lactate is to be used in conjunction with emollients and topical steroids to eczematous areas.2 These treatment recommendations are based on clinical experience at a dermatology referral clinic for patients on targeted therapies started in 2006.

Incidence and risk of xerosis with targeted anticancer therapies

Background Many targeted therapies used in the treatment of cancer can lead to the development of xerosis, but the incidence and relative risk of xerosis have not been ascertained. Objective We conducted a systematic review and metaanalysis of clinical trials, to ascertain the incidence and risk of developing xerosis after taking anticancer drugs. Methods The PubMed (1966-October 2013), Web of Science (January 1998-October 2013), and American Society of Clinical Oncology abstracts (2004-2013) databases were searched for clinical trials of 58 targeted agents. Results were calculated using random or fixed effects models. Results The incidences of all- and high-grade xerosis were 17.9% (95% confidence interval [CI]: 15.6-20.4%) and 1.0% (95% CI: 0.9-1.5%), respectively. The risk of developing all-grade xerosis was 2.99 (95% CI: 2.0-4.3), and it varied across different drugs (P less than .001). Limitations The reporting of xerosis may vary among clinicians and institutions, and the incidence may be affected by age, concomitant medications, comorbidities, and underlying malignancies or skin conditions. Conclusion Patients receiving targeted therapies have a significant risk of developing xerosis. Patients should be counseled and treated early for this symptom to prevent suboptimal dosing and quality of life impairment

Effects of two sources of Mexican oregano oil on performance, blood profile, carcass variables, and meat of broilers

ABSTRACT The current study was conducted to investigate the effects of Mexican oregano essential oil (MOO) extracts from Lippia berlandieri Schauer (LBS) and Poliomintha longiflora Gray (PLG) on performance, blood profiles, carcass variables, and meat composition of broilers at slaugther. A total of 360 one-day-old Ross broilers were randomly distributed into four dietary treatments with six replicate pens per treatment and 15 birds per pen. The dietary treatments were: a basal diet (control), control + 0.40 g of LBS/kg of feed, control + 0.40 g of PLG/kg, and control + 0.40 g of LBS/kg + 0.40 g of PLG/kg. Results showed that linear, quadratic, and cubic effects of days were significant in the performance variables of broilers. The treatments with LBS and PLG maintained the broiler body weight without increasing feed intake and water intake when compared with the control group. Broilers given LBS+PLG and PLG had increased blood leukocytes, lymphocytes, low-density lipoprotein, and hot carcass yields. In meat composition, treatments with PLG and LBS+PLG presented similar breast protein content compared with the control treatment. Supplementation with these two MOO exhibits positive effects on broiler performance, blood profiles, carcass traits, and meat composition. These two MOO may be promising feed supplements as growth promoters and enhancers of meat quality in broiler production