A novel gene (FAM20B encoding glycosaminoglycan xylosylkinase) for neonatal short limb dysplasia resembling Desbuquois dysplasia.

Desbuquois dysplasia (DBQD) is an autosomal recessive heterogeneous disorder characterized by joint laxity and skeletal changes, including a distinctive monkey-wrench appearance of the femora, advanced carpal ossification, and abnormal patterning of the preaxial digits. Two genes for DBQD (CANT1 encoding calcium-activated nucleotidase-1 and XYLT1 encoding xylosyltransferase-1) have been reported. We propose a novel gene for neonatal short limb dysplasia resembling DBQD, based on the phenotype and genotype of two affected siblings. The affected boy and girl died in early infancy and shortly after birth, respectively. The clinical hallmarks included mid-face hypoplasia, thoracic hypoplasia with respiratory failure, very short stature (approximately -7 SD of birth length) with mesomelic shortening of the limbs, and multiple dislocations of the large joints. Radiological examinations showed prominent lesser trochanter, flared metaphyses of the long bones, and joint dislocations. The affected boy had preaxial digital hypoplasia, and the affected girl showed overlapping and syndactyly of the preaxial digits. Molecular analyses of the girl showed compound heterozygous variants in FAM20B (NM_014864: c.174_178delTACCT p.T59Afs*19/c.1038delG p.N347Mfs*4). FAM20B encodes glycosaminoglycan xylosylkinase, which acts downstream of xylosyltransferase-1. Given the fact that FAM20B deficiency causes skeletal phenotypes in mice and zebrafish, these variants are highly probable to be pathogenic.

Mutations in Biosynthetic Enzymes for the Protein Linker Region of Chondroitin/Dermatan/Heparan Sulfate Cause Skeletal and Skin Dysplasias.

Glycosaminoglycans, including chondroitin, dermatan, and heparan sulfate, have various roles in a wide range of biological events such as cell signaling, cell proliferation, tissue morphogenesis, and interactions with various growth factors. Their polysaccharides covalently attach to the serine residues on specific core proteins through the common linker region tetrasaccharide, -xylose-galactose-galactose-glucuronic acid, which is produced through the stepwise addition of respective monosaccharides by four distinct glycosyltransferases. Mutations in the human genes encoding the glycosyltransferases responsible for the biosynthesis of the linker region tetrasaccharide cause a number of genetic disorders, called glycosaminoglycan linkeropathies, including Desbuquois dysplasia type 2, spondyloepimetaphyseal dysplasia, Ehlers-Danlos syndrome, and Larsen syndrome. This review focused on recent studies on genetic diseases caused by defects in the biosynthesis of the common linker region tetrasaccharide.

Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders.

Proteoglycans (PGs) are a major component of the extracellular matrix in many tissues and function as structural and regulatory molecules. PGs are composed of core proteins and glycosaminoglycan (GAG) side chains. The biosynthesis of GAGs starts with the linker region that consists of four sugar residues and is followed by repeating disaccharide units. By exome sequencing, we found that B3GALT6 encoding an enzyme involved in the biosynthesis of the GAG linker region is responsible for a severe skeletal dysplasia, spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1). B3GALT6 loss-of-function mutations were found in individuals with SEMD-JL1 from seven families. In a subsequent candidate gene study based on the phenotypic similarity, we found that B3GALT6 is also responsible for a connective tissue disease, Ehlers-Danlos syndrome (progeroid form). Recessive loss-of-function mutations in B3GALT6 result in a spectrum of disorders affecting a broad range of skeletal and connective tissues characterized by lax skin, muscle hypotonia, joint dislocation, and spinal deformity. The pleiotropic phenotypes of the disorders indicate that B3GALT6 plays a critical role in a wide range of biological processes in various tissues, including skin, bone, cartilage, tendon, and ligament.

Coordinated expression of MMPs and TIMPs in rat knee intra-articular tissues after ACL injury.

Anterior cruciate ligament (ACL) has poor healing ability and an injured ACL would induce the degeneration of other intra-articular connective tissues. However, the coordinated expression and activities of matrix metalloproteinase (MMPs) in intra-articular tissues induced by ACL rupture were poorly understood. With a rat ACL rotating injury model, we found that after ACL injury, the mRNA levels of MMP-13, TIMP-1, and CD147 were significantly elevated in ACL, posterior cruciate ligament (PCL), synovium, meniscus, and cartilage. Also, MMP-2 activity was also elevated significantly in a time-dependent manner in all intra-articular tissues. Synovium showed the most capability to release MMPs, whereas ACL showed the highest MMP-13/TIMP-1 ratio. Generic MMP activity assay and zymography showed time dependent elevation of MMP activities in synovial fluids (SF). We concluded that the ACL injury would induce a coordinated response of intra-articular tissues to express MMPs, TIMPs, and CD147. The MMP activities in the microenvironment in SF would accumulate, released by all the intra-articular tissues, which would contribute to the knee damage and degeneration induced by ACL injury.

Is joint hypermobility important in prepubertal children?

The purpose of this study was to investigate serum prolidase activity and its relationship with collagen metabolism and joint hypermobility, and to determine the prevalence and characteristics of joint hypermobility in prepubertal children. Serum prolidase activity was measured spectrophotometrically. Joint hypermobility was defined using Beighton criteria. The children underwent complete history and physical examination. Serum levels of prolidase were lower in the hypermobile group compared with controls and no statistical difference (1,598.61 +/- 54.99, 1,741.89 +/- 57.54; P > 0.05). However, there was significant negative correlation between prolidase level and Beighton score (r = -0.295, P = 0.002). The prevalence of hypermobility was distributed as follows: >or=4, 39.3%; >or=5, 22.7%; >or=6, 13.3%. There was correlation between joint hypermobility and pes planus (P = 0.006), arthralgia (P = 0.042), and musculoskeletal disorders in mother and/or father (P < 0.001). The decrease in prolidase activity may be related with collagen metabolism in joint hypermobility Therefore, joint hypermobility appeared to warrant further investigation due to concomitant signs and symptoms.

The effects of the menstrual cycle on anterior knee laxity: a systematic review.

Female athletes are at a 4- to 6-fold increased risk of anterior cruciate ligament (ACL) injury compared with male athletes. There are several medical, emotional and financial burdens associated with these injuries. Sex hormones may be involved in the ACL injury disparity, with potential associations reported between phases of the menstrual cycle and ACL injury rates. The reported relationships between ACL injury and menstrual status may be related to associated changes in ligament mechanical properties from cyclic fluctuations of female sex hormones. A PubMed electronic database literature search, including MEDLINE (1966-2005) and CINAHL (1982-2005), with the search terms 'menstrual cycle' and 'knee laxity' was used for this systematic review. Studies were included in this systematic review if they were prospective cohort studies and investigated the association between the menstrual cycle and anterior knee laxity in females. Nine prospective cohort studies, published as 11 articles, were included in the systematic review. Six of nine studies reported no significant effect of the menstrual cycle on anterior knee laxity in women. Three studies observed significant associations between the menstrual cycle and anterior knee laxity. These studies all reported the finding that laxity increased during the ovulatory or post-ovulatory phases of the cycle. A meta-analysis, which included data from all nine reviewed studies, corroborated this significant effect of cycle phase on knee laxity (F-value = 56.59, p = 0.0001). In the analyses, the knee laxity data measured at 10-14 days was >15-28 days which was >1-9 days. Future studies testing the relationship between the menstrual cycle and potentially associated parameters should consider the limitations outlined in this article and control for potential biases and confounders. Power analyses should be utilised. Subjects should be randomly entered into the studies at alternate points in the cycle, and standard and consistent data acquisition and reporting methods should be utilised. Future studies should clearly define what constitutes a 'normal' cycle and appropriate control subjects should be utilised. Furthermore, there is a need to define cycle phase (and timing within cycle phase) with actual hormone levels rather than a day of the cycle. Although hormone confirmations were provided in many of the studies that selected specific days to depict a particular cycle for all women, it is unknown from these data if they truly captured times of peak hormone values in all women. A combined systematic review and meta-analysis of the literature indicate that the menstrual cycle may have an effect on anterior-posterior laxity of the knee; however, further investigation is needed to confirm or reject this hypothesis.

Nitroxide synthase activity as a marker of early stages of experimental cartilage dysmetabolism.

Time course of nitroxide synthase activity in the knee joint cartilage was studied in animals with experimental anterior instability of the knee joint. A significant increase in nitroxide synthase activity in chondrocytes was paralleled by a progressive decrease in glycosaminoglycan content in the cartilaginous matrix and subsequent destruction of the cartilage cytoarchitectonics.

[Nitric oxide synthase and apoptosis activity in chondrocytes of articular cartilage in posttraumatic knee instability]. / Aktivnost' nitroksidsintazy i apoptoza v khondrotsitakh sustavnogo khriashcha pri posttravmaticheskoi nestabil'nosti kolennogo sustava.

The dynamics of nitric oxide synthase (NOS) and apoptosis activity was studied in the in chondrocytes of articular cartilage of the patients with posttraumatic knee instability. Statistically significant increase of chondrocyte NOS activity was detected in the earliest period after the trauma (1.5 months). This was accompanied by the appearance of a great number of apoptotic cells in the zones of the cartilage with high NOS activity. Remarkably, these changes developed at the same time with statistically significant decrease of total matrix glycosaminoglycan content. These results suggest that there is a NOS-dependent signaling way of apoptosis that could participate in the development of early dystrophic changes in the cartilage.