Junzhou Tang

BACKGROUND AND AIM: Controlled attenuation parameter (CAP) is a novel ultrasound-based elastography method for detection of steatosis severity. This meta-analysis aimed to assess the performance of CAP. METHODS: PubMed, the Cochrane Library, and the Web of Knowledge were searched to find studies, published in English, relating to accuracy evaluations of CAP for detecting stage 1 (S1), stage 2 (S2), or stage 3 (S3) hepatic steatosis which was diagnosed by liver biopsy. Sensitivities, specificities, and hierarchical summary receiver operating characteristic (HSROC) curves were used to examine CAP performance. The clinical utility of CAP was also evaluated. RESULTS: Nine studies, with 11 cohorts were analyzed. The summary sensitivities and specificities values were 0.78 (95% confidence interval [CI], 0.69-0.84) and 0.79 (95% CI, 0.68-0.86) for ≥ S1, 0.85 (95% CI, 0.74-0.92) and 0.79 (95% CI, 0.71-0.85) for ≥ S2, and 0.83 (95% CI, 0.76-0.89) and 0.79 (95% CI, 0.68-0.87) for ≥ S3. The HSROCs were 0.85 (95% CI, 0.81-88) for ≥ S1, 0.88 (95% CI, 0.85-0.91) for ≥ S2, and 0.87 (95% CI, 0.84-0.90) for ≥ S3. Following a "positive" measurement (over the threshold value) for ≥ S1, ≥ S2, and ≥ S3, the corresponding post-test probabilities for the presence of steatosis (pretest probability was 50%) were 78%, 80% and 80%, respectively; if the values were below these thresholds ("negative" results), the post-test probabilities were 22%, 16%, and 17%, respectively. CONCLUSIONS: CAP has good sensitivity and specificity for detecting hepatic steatosis; however, based on a meta-analysis, CAP was limited in their accuracy of steatosis, which precluded widespread use in clinical practice.

OBJECTIVE: Fibroblast growth factor (FGF) signaling is involved in articular cartilage homeostasis. This study was undertaken to investigate the role and mechanisms of FGF receptor 3 (FGFR-3) in the pathogenesis of osteoarthritis (OA) caused by surgery and aging in mice. METHODS: FGFR-3 was conditionally deleted or activated in articular chondrocytes in adult mice subjected to surgical destabilization of the medial meniscus (DMM). A mouse model of human achondroplasia was also used to assess the role of FGFR-3 in age-associated spontaneous OA. Knee joint cartilage was histologically evaluated and scored using the Osteoarthritis Research Society International system. The expression of genes associated with articular cartilage maintenance was quantitatively evaluated in hip cartilage explants. The effect of inhibiting Indian hedgehog (IHH) signaling in Fgfr3-deficient explants was analyzed. RESULTS: Conditional Fgfr3 deletion in mice aggravated DMM-induced cartilage degeneration. Matrix metalloproteinase 13 and type X collagen levels were up-regulated, while type II collagen levels were down-regulated, in the articular cartilage of these mice. Conversely, FGFR-3 activation attenuated cartilage degeneration induced by DMM surgery and age. IHH signaling and runt-related transcription factor 2 levels in mouse articular chondrocytes were up-regulated in the absence of Fgfr3, while inhibition of IHH signaling suppressed the increases in the expression of Runx2, Mmp13, and other factors in Fgfr3-deficient mouse cartilage explants. CONCLUSION: Our findings indicate that FGFR-3 delays OA progression in mouse knee joints at least in part via down-regulation of IHH signaling in articular chondrocytes.

Dicer participates in heterochromatin formation in fission yeast and plants. However, whether it has a similar role in mammals remains controversial. Here we showed that the human Dicer protein interacts with SIRT7, an NAD(+)-dependent H3K18Ac (acetylated lysine 18 of histone H3) deacetylase, and holds a proportion of SIRT7 in the cytoplasm. Dicer knockdown led to an increase of chromatin-associated SIRT7 and simultaneously a decrease of cytoplasmic SIRT7, while its overexpression induced SIRT7 reduction in the chromatin-associated fraction and increment in the cytoplasm. Furthermore, DNA damaging agents promoted Dicer expression, leading to decreased level of chromatin-associated SIRT7 and increased level of H3K18Ac, which can be alleviated by Dicer knockdown. Taken together with that H3K18Ac was exclusively associated with the chromatin, our findings suggest that Dicer induction by DNA damaging treatments prevents H3K18Ac deacetylation, probably by trapping more SIRT7 in the cytoplasm.

Chondrogenesis can regulate bone formation. Fibroblast growth factor receptor 3, highly expressed in chondrocytes, is a negative regulator of bone growth. To investigate whether chondrocyte FGFR3 regulates osteogenesis, thereby contributing to postnatal bone formation and bone remodeling, mice with conditional knock-out of Fgfr3 in chondrocytes (mutant (MUT)) were generated. MUT mice displayed overgrowth of bone with lengthened growth plates. Bone mass of MUT mice was significantly increased at both 1 month and 4 months of age. Histological analysis showed that osteoblast number and bone formation were remarkably enhanced after deletion of Fgfr3 in chondrocytes. Chondrocyte-osteoblast co-culture assay further revealed that Fgfr3 deficiency in chondrocytes promoted differentiation and mineralization of osteoblasts by up-regulating the expressions of Ihh, Bmp2, Bmp4, Bmp7, Wnt4, and Tgf-β1, as well as down-regulating Nog expression. In addition, osteoclastogenesis was also impaired in MUT mice with decreased number of osteoclasts lining trabecular bone, which may be related to the reduced ratio of Rankl to Opg in Fgfr3-deficient chondrocytes. This study reveals that chondrocyte FGFR3 is involved in the regulation of bone formation and bone remodeling by a paracrine mechanism.

Most cartilaginous tumors are formed during skeletal development in locations adjacent to growth plates, suggesting that they arise from disordered endochondral bone growth. Fibroblast growth factor receptor (FGFR)3 signaling plays essential roles in this process; however, the role of FGFR3 in cartilaginous tumorigenesis is not known. In this study, we found that postnatal chondrocyte-specific Fgfr3 deletion induced multiple chondroma-like lesions, including enchondromas and osteochondromas, adjacent to disordered growth plates. The lesions showed decreased extracellular signal-regulated kinase (ERK) activity and increased Indian hedgehog (IHH) expression. The same was observed in Fgfr3-deficient primary chondrocytes, in which treatment with a mitogen-activated protein kinase (MEK) inhibitor increased Ihh expression. Importantly, treatment with an inhibitor of IHH signaling reduced the occurrence of chondroma-like lesions in Fgfr3-deficient mice. This is the first study reporting that the loss of Fgfr3 function leads to the formation of chondroma-like lesions via downregulation of MEK/ERK signaling and upregulation of IHH, suggesting that FGFR3 has a tumor suppressor-like function in chondrogenesis.