Novel genetic variants for cartilage thickness and hip osteoarthritis

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies

The cranial nerves

With the exception of the olfactory and optic nerves, all cranial nerves enter or leave the brain stem. Three of the cranial nerves are purely sensory (I, II and VIII), five are motor (III, IV, VI, XI and XII) and the remaining nerves (V, VII, IX and X) are mixed. The olfactory nerve will be discussed in Chap. 14, the optic nerve in Chap. 8 and the cochlear nerve in Chap. 7. The nuclei of the cranial nerves are arranged in an orderly, more or less columnar fashion in the brain stem: motor nuclei, somatomotor, branchiomotor and visceromotor (parasympathetic), derived from the basal plate, are located medially, whereas sensory nuclei, somatosensory, viscerosensory and vestibulocochlear, derived from the alar plate, are found lateral to the sulcus limitans. The cranial nerves innervate structures in the head and neck as well as visceral organs in the thorax and abdomen. The cranial nerves control eye movements, mastication, vocalization, facial expression, respiration, heart rate and digestion. One or several of the cranial nerves are often involved in lesions of the brain stem, of which the location can usually be determined if the topographical anatomy of the cranial nerves and their nuclei is known. Several examples are shown in Clinical cases. Following a few notes on the development of the brain stem and congenital cranial dysinnervation disorders (Sect. 6.2), the following structures will be discussed: (1) ocular motor nerves and the effects of lesions of individual ocular motor nerves (Sect. 6.3); (2) eye movements and some disorders affecting them (Sect. 6.4); (3) the trigeminal nerve and changes in the blink reflex (Sect. 6.5); (4) the facial nerve and peripheral facial nerve paralysis (Sect. 6.6); (5) the gustatory system (Sect. 6.7); (6) the vestibulocochlear nerve, vestibular control and some peripheral and central vestibular syndromes (Sect. 6.8); and (7) the last four cranial nerves and some disorders affecting them (Sects. 6.9 and 6.10). The English terms of the Terminologia Neuroanatomica are used throughout.</p

Mutations in the interglobular domain of aggrecan alter matrix metalloproteinase and aggrecanase cleavage patterns - Evidence that matrix metalloproteinase cleavage interferes with aggrecanase activity

We have expressed G1-G2 mutants with amino acid changes at the DIPEN(341) downward arrow(342)FFGVG and ITEGE(373) downward arrow(374)ARGSV cleavage sites, in order to investigate the relationship between matrix metalloproteinase (MMP) and aggrecanase activities in the interglobular domain (IGD) of aggrecan. The mutation DIPEN(341) to DIGSA(341) partially blocked cleavage by MMP-13 and MMP-8 at the MMP site, while the mutation (342)FFGVG to (342)GTRVG completely blocked cleavage at this site by MMP-1, -2, -3, -7, -8, -9, -13, -14. Each of the MMP cleavage site mutants, including a four-amino acid deletion mutant lacking residues ENFF(343), were efficiently cleaved by aggrecanase, suggesting that the primary sequence at the MMP site had no effect on aggrecanase activity in the IGD. The mutation (374)ARGSV to (374)NVYSV completely blocked cleavage at the aggrecanase site by aggrecanase, MMP-8 and atrolysin C but had no effect on the ability of MMP-8 and MMP-13 to cleave at the Asn(341) downward arrowPhe bond. Susceptibility to atrolysin C cleavage at the MMP site was conferred in the DIGSA(341) mutant but absent in the wild-type, (342)GTRVG, (374)NVYSV, and deletion mutants. To further explore the relationship between MMP and aggrecanase activities, sequential digest experiments were done in which MMP degradation products were subsequently digested with aggrecanase and vice versa. Aggrecanase-derived G1 domains with ITEGE(373) C termini were viable substrates for MMPs; however, MMP-derived G2 fragments were resistant to cleavage by aggrecanase. A 10-mer peptide FVDIPENFFG, which is a substrate analogue for the MMP cleavage site, inhibited aggrecanase cleavage at the Glu(373) downward arrowAla bond. This study demonstrates that MMPs and aggrecanase have unique substrate recognition in the IGD of aggrecan and suggests that sequences at the C terminus of the DIPEN(341) G1 domain may be important for regulating aggrecanase cleavage

Magnetic resonance imaging measurement of knee cartilage volume in a multicentre study

Objective. To investigate the variability between different high-field scanners in magnetic resonance imaging (MRI) measurement of knee cartilage volume in healthy female volunteers. Methods. Five volunteers had both knees scanned using three different MRI scanners. Cartilage volume in each compartment was measured from the images by image segmentation. The data were analysed using analysis of variance models. Results. The mean total cartilage volume of the 10 knees scanned at three different centres was 16.15, 16.40 and 15.63ml for the Siemens, GE and Philips scanners respectively. Small systematic differences were seen in the total knee cartilage volume results. Conclusions. Although there were small systematic differences in knee cartilage volume, the three MRI scanners gave broadly similar results. KEY WORDS: MRI, Knee cartilage, Multicentre clinical trials. In osteoarthritis (OA), the current standard technique for mea-suring structural changes in the joint approved by the US Food and Drug Administration is X-radiography of joint space width [1]. However, this technique lacks precision, particularly in short-term studies: it has been estimated that several hundred patients woul