The role of WWP1 and WWP2 in bone/cartilage development and diseases.

Bone and cartilage diseases are often associated with trauma and senescence, manifested as pain and limited mobility. The repair of bone and cartilage lesion by mesenchymal stem cells is regulated by various transcription factors. WW domain-containing protein 1 (WWP1) and WW domain-containing protein 2 (WWP2) are named for WW domain which recognizes PPXY (phono Ser Pro and Pro Arg) motifs of substrate. WWP1and WWP2 are prominent components of the homologous to the E6-AP carboxyl terminus (HECT) subfamily, a group of the ubiquitin ligase. Recently, some studies have found that WWP1 and WWP2 play an important role in the pathogenesis of bone and cartilage diseases and regulate the level and the transactivation of various transcription factors through ubiquitination. Therefore, this review summarizes the distribution and effects of WWP1 and WWP2 in the development of bone and cartilage, discusses the potential mechanism and therapeutic drugs in bone and cartilage diseases such as osteoarthritis, fracture, and osteoporosis.

Role of Interleukin-36 in inflammatory joint diseases. / ç™½ä»‹ç´ -36åœ¨å ³èŠ‚ç‚Žæ€§ç–¾ç— ä¸­çš„ä½œç”¨.

Interleukin (IL)-36 is a family of cytokines that belongs to the larger IL-1 superfamily. IL-36 agonist/antagonist binds to the interleukin-36 receptor involving in physiological inflammation regulation and pathogenesis of many inflammatory diseases. In inflammatory joint diseases, the expression of IL-36 changes, and some studies have initially explored the role of IL-36 in these diseases. In psoriatic arthritis, IL-36 signal mediates plasma cell and fibroblast-like synoviocyte crosstalk presenting IL-36 agonist/antagonist imbalance. In rheumatoid arthritis, IL-36 agonists induce fibroblast-like synoviocyte to produce pro-inflammatory factors, while IL-36 antagonist deficiency leads to lesion progression. In osteoarthritis, IL-36 agonists induce chondrocytes to produce catabolic enzymes and pro-inflammatory factors. This article reviews the expression and function of IL-36 in different inflammatory joint diseases to provide a reference for revealing their pathogenic mechanisms and discovering therapeutic targets.

Research progress on tissue engineering in repairing tempomandibular joint.

Temporomandibular joint osteoarthritis (TMJOA) is mainly manifested as perforation of temporomandibular joint disc (TMJD) and destruction of condylar osteochondral complex (COCC). In recent years, tissue engineering technology has become one of the effective strategies in repairing this damage. With the development of scaffold material technology, composite scaffolds have become an important means to optimize the performance of scaffolds with the combined advantages of natural materials and synthetic materials. The gelling method with the minimally invasive concept can greatly solve the problems of surgical trauma and material anastomosis, which is beneficial to the clinical transformation of temporomandibular joint tissue engineering. Extracellular matrix scaffolds technology can solve the problem of scaffold source and maximize the simulation of the extracellular environment, which provides an important means for the transformation of temporo joint tissue engineering to animal level. Due to the limitation of the source and amplification of costal chondrocytes, the use of mesenchymal stem cells from different sources has been widely used for temporomandibular joint tissue engineering. The fibrochondral stem cells isolated from surface layer of articular cartilage may provide one more suitable cell source. Transforming growth factor ß superfamily, due to its osteochondrogenesis activity has been widely used in tissue engineering, and platelet-rich derivative as a convenient preparation of compound biological factor, gradually get used in temporomandibular joint tissue engineering. With the deepening of research on extracellular microenvironment and mechanical stimulation, mesenchymal stem cells, exosomes and stress stimulation are increasingly being used to regulate the extracellular microenvironment. In the future, the combination of complex bioactive factors and certain stress stimulation may become a trend in the temporomandibular joint tissue engineering research. In this article, the progress on tissue engineering in repairing COCC and TMJD, especially in scaffold materials, seed cells and bioactive factors, are reviewed, so as to provide information for future research design and clinical intervention.

Therapeutic application of 3B-PEG injectable hydrogel/Nell-1 composite system to temporomandibular joint osteoarthritis.

This study aims to construct a composite system of the tri-block polyethylene glycol injectable hydrogel (3B-PEG IH) and neural epithelial growth factor-like protein 1 (Nell-1), and to analyze its therapeutic effect on temporomandibular joint osteoarthritis (TMJOA). Sol-gel transition temperature was measured via inverting test. The viscoelastic modulus curves was measured by rheometer. Degradation and controlled release profiles of 3B-PEG IH were drawnin vitro.In vivogel retention and biocompatibility were completed subcutaneously on the back of rats. After primary chondrocytes were extracted and identified, the cell viability in 3B-PEG IH was measured. Evaluation of gene expression in hydrogel was performed by real-time polymerase chain reaction. TMJOA rabbits were established by intra-articular injection of type II collagenase. Six weeks after composite systems being injected, gross morphological score, micro-CT, histological staining and grading were evaluated. The rusults showed that different types of 3B-PEG IH all reached a stable gel state at 37 °C and could support the three-dimensional growth of chondrocytes, but poly(lactide-co-caprolactone)-block-poly(ethyleneglycol)-block-poly(lactide-co-caprolactone) (PLCL-PEG-PLCL) hydrogel had a wider gelation temperature range and better hydrolytic stability for about 4 weeks. Its controlled release curve is closest to the zero-order release kinetics.In vitro, PLCL-PEG-PLCL/Nell-1 could promote the chondrogenic expression and reduce the inflammatory expression.In vivo, TMJOA rabbits were mainly characterized by the disorder of cartilage structure and the destruction of subchondral bone. However, PLCL-PEG-PLCL/Nell-1 could reverse the destruction of the subchondral trabecula, restore the fibrous and proliferative layers of the surface, and reduce the irregular hyperplasia of fibrocartilage layer. In conclusion, by comparing the properties of different 3B-PEG IH, 20 wt% PLCL-PEG-PLCL hydrogel was selected as the most appropriate material. PLCL-PEG-PLCL/Nell-1 composite could reverse osteochondral damage caused by TMJOA, Nfatc1-Runx3 signaling pathway may play a role in it. This study may provide a novel, minimally-invasive therapeutic strategy for the clinical treatment of TMJOA.

Cardiac disorders and structural brain abnormalities are commonly associated with hypospadias in children with neurodevelopmental disorders.

The objective of our study was to use an established cohort of boys to investigate common patterns of malformations in those with hypospadias. We performed a retrospective review of the phenotype of participants in the Deciphering Developmental Disorders Study with neurodevelopmental delay and an 'Abnormality of the genital system'. This group was divided into two subgroups: those with hypospadias and without hypospadias. Associated phenotypes of the two subgroups were compared and analysed. Of the 166 Deciphering Developmental Disorders participants with hypospadias and neurodevelopmental delay, 47 (28%) had cardiovascular and 40 (24%) had structural brain abnormalities. The rate of cardiovascular abnormalities in those with neurodevelopmental delay and genital abnormalities other than hypospadias (N = 645) was lower at 19% (P = 0.001). In addition, structural brain malformations were higher at 24% in the hypospadias group versus 15% in the group without hypospadias (P = 0.002). The constellation of these features occured at a higher rate in the hypospadias group versus the no hypospadias group (P = 0.038). In summary, this is the first study to indicate that cardiovascular and brain abnormalities are frequently encountered in association with hypospadias in children with neurodevelopmental disorders. Not only do these associations provide insight into the underlying aetiology but also they highlight the multisystem involvement in conditions with hypospadias.

Fractures and Linear Growth in a Nationwide Cohort of Boys With Duchenne Muscular Dystrophy With and Without Glucocorticoid Treatment: Results From the UK NorthStar Database.

Importance: Based on studies with relatively small sample size, fragility fractures are commonly reported in glucocorticoid (GC)-treated boys with Duchenne muscular dystrophy (DMD). Objective: To determine the fracture burden and growth impairment in a large contemporary cohort of boys with DMD in the United Kingdom and in relation to GC regimen. Design, Setting, and Participants: A retrospective review of fracture morbidity and growth from 832 boys with DMD in the UK NorthStar database (2006-2015), which systematically captures information from 23 participating centers. A total of 564 boys had more than 1 visit. No numbers of boys who refused were collected, but informal data from 2 centers in London and from Scotland show that refusal is very low. Data were analyzed between October 2006 and October 2015. Main Outcomes and Measures: Fracture incidence rate per 10 000 person-years was determined. Cox regression analysis was used to identify factors associated with first fracture. Results: Median age at baseline was 6.9 years (interquartile range, 4.9-7.2 years). At baseline, new fractures were reported in 7 of 564 participants (1.2%). During a median follow-up of 4 years (interquartile range, 2.0-6.0 years), incident fractures were reported in 156 of 564 participants (27.7%), corresponding to an overall fracture incidence rate of 682 per 10 000 person-years (95% CI, 579-798). The highest fracture incidence rate was observed in those treated with daily deflazacort at 1367 per 10 000 person-years (95% CI, 796-2188). After adjusting for age at last visit, mean hydrocortisone equivalent dose, mobility status, and bisphosphonate use prior to first fracture, boys treated with daily deflazacort had a 16.0-fold increased risk for first fracture (95% CI, 1.4-180.8; P = .03). Using adjusted regression models, change in height standard deviation scores was -1.6 SD lower (95% CI, -3.0 to -0.1; P = .03) in those treated with daily deflazacort compared with GC-naive boys, whereas there were no statistical differences in the other GC regimen. Conclusions and Relevance: In this large group of boys with DMD with longitudinal data, we document a high fracture burden. Boys treated with daily deflazacort had the highest fracture incidence rate and the greatest degree of linear growth failure. Clinical trials of primary bone protective therapies and strategies to improve growth in boys with DMD are urgently needed, but stratification based on GC regimen may be necessary.

Association Between Extra-Genital Congenital Anomalies and Hypospadias Outcome.

Extra-genital congenital anomalies are often present in cases of hypospadias, but it is unclear whether they have an association with the outcome of hypospadias surgery. The aim of this study was to review all hypospadias cases that had surgery between 2009 and 2015 at a single centre and identify clinical determinants of the surgical outcome. An extra-genital congenital anomaly was reported in 139 (22%) boys and 62 (10%) had more than 1 anomaly. Of the 626 boys, 54 (9%), including 44 with proximal hypospadias, had endocrine as well as limited genetic evaluation. Of these, 10 (19%) had a biochemical evidence of hypogonadism and 5 (9%) had a molecular genetic abnormality. At least 1 complication was reported in 167 (27%) patients, with 20% of complications (most frequently fistula) occurring after 2 years of surgery. The severity of hypospadias and the existence of other anomalies were clinical factors that were independently associated with an increased risk of complications (p < 0.001). In conclusion, complications following surgery are more likely in those cases that are proximal or who have additional extra-genital anomalies. To understand the biological basis of these complications, there is a greater need to understand the aetiology of such cases.

Fractures and bone health monitoring in boys with Duchenne muscular dystrophy managed within the Scottish Muscle Network.

There are limited reports of radiologically confirmed fractures and bone health monitoring in with Duchenne muscular dystrophy. We performed a retrospective study of 91 boys, with a median age of 11.0 years, who are currently managed in Scotland with the aim to assess the frequency of radiologically confirmed fractures and report on bone health monitoring in relation to International Care Consensus Guidance. Of these boys, 59 (65%) were receiving glucocorticoid (GC) therapy and 23 (25%) had received previous treatment. Of those currently on GC, 37 (63%) had an assessment of bone mineral density and none had routine imaging for vertebral fractures during the study period. Of the 91 boys, 44 (48%) had sustained at least one symptomatic radiographically confirmed fracture. The probability of sustaining a first symptomatic fracture was 50% by 12.8 years old (95%CI: 12.1, 13.6). The most common sites for non-vertebral fracture were the femur and tibia. In this review of boys with DMD, almost half had sustained at least one radiologically confirmed symptomatic fracture. There is a need for standardized bone health monitoring in DMD that includes routine imaging of the spine to identify vertebral fractures, given the persistence of insult to the skeleton in these boys.