Cheilectomy for Treatment of Symptomatic Distal Interphalangeal Joint Osteoarthritis: A Review of 78 Patients.

PURPOSE: To determine whether open cheilectomy and debridement of the distal interphalangeal (DIP) joint is a safe and effective alternative to joint arthrodesis for the treatment of symptomatic osteoarthritis. METHODS: Seventy-eight patients with symptomatic DIP joint osteoarthritis and with a minimum follow-up of 24 months were retrospectively reviewed. Preoperative radiographs were graded. Open cheilectomy and debridement of the DIP joint was performed in all patients. The DIP joint was immobilized for 4 weeks after surgery. Patients were evaluated clinically and radiographically. Visual analog scale pain scores and range of motion were assessed. RESULTS: At a median final follow-up of 36 months (minimum, 24 months), there was a significant improvement in mean visual analog scale pain scores from 8 to 1. Distal interphalangeal joint flexion contracture was improved by a mean of 6° and DIP joint range of motion was improved by a mean of 20°. No postoperative infections or other complication were noted. No reoperations were required/performed during the follow-up period. CONCLUSIONS: Open DIP joint cheilectomy is a safe and effective alternative to DIP joint arthrodesis in patients with symptomatic osteoarthritis who wish to preserve joint motion. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Distal Biceps Tendon Anatomic Repair.

Distal biceps injuries, which usually occur in active middle-aged men, can result in chronic pain and loss of supination and flexion strength3,4. Surgical repair of a ruptured distal biceps tendon can reliably decrease pain and improve strength compared with nonoperative management3,4. However, even following successful healing and rehabilitation of a surgically repaired biceps tendon, full supination strength is rarely restored5-7. The expected outcome following distal biceps repair using a traditional anterior approach is a measurable loss of rotational strength, especially from neutral to supinated positions5,7. This deficit can lead to difficulty with occupational and recreational activities5,8. The center of an uninjured biceps tendon inserts into the radial tuberosity 6.7 mm anterior to its apex9,10. This posterior location forces the biceps tendon to wrap around the radial protuberance during pronation, thus utilizing the protuberance as a mechanical cam during forceful forearm supination10,11. The distal biceps tendon comprises a medial short head and lateral long head; the 2 heads are continuations of the proximal muscles2,20,21. The short head inserts distal to the long head on their radial attachment site2,20,21. Performing a distal biceps repair via an anterior approach typically places the center of the reattachment site 12.9 mm anterior to its apex or approximately 6 mm anterior to an uninjured control tendon9. This shifts the repair site from its anatomic location (posterior to the radial protuberance) to a new nonanatomic location (on top of the protuberance). This anterior reattachment location decreases the cam effect of the radial protuberance, resulting in an average supination loss of 10% in neutral rotation and 33% in 60° of supination7,10. A posterior approach to the radial tuberosity using 2 separate intramedullary buttons for the short and long heads reliably positions the distal biceps insertion at its anatomic footprint, which is posterior to the radial protuberance9,10,11. This technique has been named the distal biceps tendon anatomic repair. Not only does it restore the normal supination cam effect of the radial protuberance, but it also provides superior initial fixation strength, with load to failure strength similar to the native tendon1. The distal biceps anatomic repair can be divided into the following 9 key steps: Step 1: Preoperative planning; Step 2: Positioning; Step 3: Identifying and retrieving the tendon; Step 4: Preparing the 2 heads of the tendon; Step 5: Posterior exposure of tendon footprint; Step 6: Drilling the short and long-head drill holes; Step 7: Passage of the tendon; Step 8: Unicortical button fixation; Step 9: Alternative fixation: cortical trough; and Step 10: Postoperative management.

ADAMTS-7 forms a positive feedback loop with TNF-α in the pathogenesis of osteoarthritis.

OBJECTIVE: To examine the expression of ADAMTS-7 during the progression of osteoarthritis (OA), defining its role in the pathogenesis of OA, and elucidating the molecular events involved. METHODS: ADAMTS-7 expression in cartilage of a rat OA model was assayed using immunohistochemistry. Cartilage-specific ADAMTS-7 transgenic mice and ADAMTS-7 small interfering (si)RNA knockdown mice were generated and used to analyse OA progression in both spontaneous and surgically induced OA models. Cartilage degradation and OA was evaluated using Safranin-O staining, immunohistochemistry, ELISA and western blotting. In addition, mRNA expression of tumour necrosis factor (TNF)-α and metalloproteinases known to be involved in cartilage degeneration in OA was analysed. Furthermore, the transactivation of ADAMTS-7 by TNF-α and its downstream NF-κB signalling was measured using reporter gene assay. RESULTS: ADAMTS-7 expression was elevated during disease progression in the surgically induced rat OA model. Targeted overexpression of ADAMTS-7 in chondrocytes led to chondrodysplasia characterised by short-limbed dwarfism and a delay in endochondral ossification in 'young mice' and a spontaneous OA-like phenotype in 'aged' mice. In addition, overexpression of ADAMTS-7 led to exaggerated breakdown of cartilage and accelerated OA progression, while knockdown of ADAMTS-7 attenuated degradation of cartilage matrix and protected against OA development, in surgically induced OA models. ADAMTS-7 upregulated TNF-α and metalloproteinases associated with OA; in addition, TNF-α induced ADAMTS-7 through NF-κB signalling. CONCLUSIONS: ADAMTS-7 and TNF-α form a positive feedback loop in the regulation of cartilage degradation and OA progression, making them potential molecular targets for prevention and treatment of joint degenerative diseases, including OA.

Prevention of atrophic nonunion by the systemic administration of parathyroid hormone (PTH 1-34) in an experimental animal model.

OBJECTIVES: Recombinant human parathyroid hormone (PTH 1-34) has been previously shown to enhance fracture healing in animal models. Here, we sought to determine whether the systemic administration of PTH 1-34 is effective in preventing atrophic fracture nonunion in a murine, surgical nonunion model. METHODS: We used an established reproducible long-bone murine fracture nonunion model by generating a midshaft femur fracture, followed by fracture distraction using an intramedullary pin and custom metallic clip to maintain a fracture gap of 1.7 mm. Mice were randomized to receive either daily intraperitoneal injections of 30 µg/kg PTH 1-34 for 14 days or saline injections. At 6 weeks after the procedure, radiographic and histologic assessment of fracture healing was performed. RESULTS: At 6 weeks after surgery, the group treated with PTH showed higher rates of bony union (50% vs 8%; P < 0.05) as assessed by radiographic analysis. Mean gap size was also significantly lower in the PTH group (1.42 vs 0.36 mm in the control group; P < 0.05). Histologic analysis of atrophic nonunions in the control group revealed a persistent fracture gap with intervening fibrous tissue. In contrast, healed subjects in the PTH-treated group had cortical bridging with mature bone and relatively little callus, which is consistent with primary intramembranous ossification. CONCLUSIONS: Daily systemic administration of recombinant PTH 1-34 increased the rate of union in a mouse atrophic nonunion model. This may have important implications for the potential clinical role of PTH 1-34 in the treatment of atrophic fracture nonunions.

GEP constitutes a negative feedback loop with MyoD and acts as a novel mediator in controlling skeletal muscle differentiation.

Granulin-epithelin precursor (GEP) is an autocrine growth factor that has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation. Here we report that GEP was expressed in skeletal muscle tissue and its level was differentially altered in the course of C2C12 myoblast fusion. The GEP expression during myoblast fusion was a consequence of MyoD transcription factor binding to several E-box (CANNTG) sequences in the 5'-flanking regulatory region of GEP gene, followed by transcription. Recombinant GEP potently inhibited myotube formation from C2C12 myoblasts whereas the knockdown of endogenous of GEP via a siRNA approach accelerated the fusion of myoblasts to myotubes. Interestingly, the muscle fibers of GEP knockdown mice were larger in number but noticeably smaller in size when compared to the wild-type. Mechanistic studies revealed that during myoblast fusion, the addition of GEP led to remarkable reductions in the expressions of muscle-specific transcription factors, including MyoD. In addition, the regulation of myotube formation by GEP is mediated by the anti-myogenic factor JunB, which is upregulated following GEP stimulation. Thus, GEP growth factor, JunB, and MyoD transcription factor form a regulatory loop and act in concert in the course of myogenesis.

Young and burgess type I lateral compression pelvis fractures: a comparison of anterior and posterior pelvic ring injuries.

The goals of this study were to find associations between anterior and posterior ring injuries, provide a descriptive comparison of pelvic ring disruptions as assessed by plain radiography, and compare the value of computed tomography (CT) over plain radiography in evaluating anterior and posterior structures. A retrospective review of radiographic reports and records identified 142 patients with pubic ramus fractures as observed by plain radiography. A statistical analysis was performed to test the associations between anterior ring injury as assessed by plain radiography and posterior ring injury as assessed by CT. Forty-five point five percent of patients with bilateral ramus fractures and 42.0% of patients with dual-ramus fractures had concomitant sacral fractures not observed on plain radiographs. These occult sacral fractures were found in only 11.1% of patients with inferior ramus fractures. The type of pubic injury on plain radiographs may be predictive of posterior ring injury, and therefore may help determine injury energy and severity, determine the need for further imaging studies, and help guide clinical management. Although CT is highly sensitive in identifying both anterior and posterior pubic ring injuries, elderly patients with simple fractures of a single pubic ramus are less likely to suffer from pelvic instability and thus may not benefit from CT.

XBP1U inhibits the XBP1S-mediated upregulation of the iNOS gene expression in mammalian ER stress response.

Upregulation of the inducible nitric oxide synthase (iNOS) gene is associated with many pathological conditions such as endoplasmic reticulum (ER) stress, and X-box binding protein 1 (XBP1) is critical in mediating ER-stress responsive genes, including iNOS. Nonetheless, the mechanism by which XBP1 regulates iNOS during ER stress remains unexplored. Here we show that the active/spliced form of XBP1 protein, XBP1S, directly binds to the AABS (A-activator-binding site) in the iNOS promoter in vitro and in living cells. XBP1S exhibits dose-dependent activation of iNOS-specific reporter gene activity and endogenous iNOS expression. XBP1S is elevated whereas the unspliced form of XBP1, XBP1U, reduced in ER stress in HepG2 cells. In addition, XBP1U binds to XBP1S and this complex is associated with the iNOS promoter in response to ER stress. Furthermore, XBP1U acts as a negative mediator and suppresses XBP1S-mediated induction of iNOS. Collectively, we present the first evidence demonstrating the regulation of iNOS gene induction by the interaction between the spliced and unspliced forms of XBP1 in response to ER stress.

Granulin-epithelin precursor binds directly to ADAMTS-7 and ADAMTS-12 and inhibits their degradation of cartilage oligomeric matrix protein.

OBJECTIVE: To determine 1) whether a protein interaction network exists between granulin-epithelin precursor (GEP), ADAMTS-7/ADAMTS-12, and cartilage oligomeric matrix protein (COMP); 2) whether GEP interferes with the interactions between ADAMTS-7/ADAMTS-12 metalloproteinases and COMP substrate, including the cleavage of COMP; 3) whether GEP affects tumor necrosis factor alpha (TNFalpha)-mediated induction of ADAMTS-7/ADAMTS-12 expression and COMP degradation; and 4) whether GEP levels are altered during the progression of arthritis. METHODS: Yeast two-hybrid, in vitro glutathione S-transferase pull-down, and coimmunoprecipitation assays were used to 1) examine the interactions between GEP, ADAMTS-7/ADAMTS-12, and COMP, and 2) map the binding sites required for the interactions between GEP and ADAMTS-7/ADAMTS-12. Immunofluorescence cell staining was performed to visualize the subcellular localization of GEP and ADAMTS-7/ADAMTS-12. An in vitro digestion assay was employed to determine whether GEP inhibits ADAMTS-7/ADAMTS-12-mediated digestion of COMP. The role of GEP in inhibiting TNFalpha-induced ADAMTS-7/ADAMTS-12 expression and COMP degradation in cartilage explants was also analyzed. RESULTS: GEP bound directly to ADAMTS-7 and ADAMTS-12 in vitro and in chondrocytes, and the 4 C-terminal thrombospondin motifs of ADAMTS-7/ADAMTS-12 and each granulin unit of GEP mediated their interactions. Additionally, GEP colocalized with ADAMTS-7 and ADAMTS-12 on the cell surface of chondrocytes. More importantly, GEP inhibited COMP degradation by ADAMTS-7/ADAMTS-12 in a dose-dependent manner through 1) competitive inhibition through direct protein-protein interactions with ADAMTS-7/ADAMTS-12 and COMP, and 2) inhibition of TNFalpha-induced ADAMTS-7/ADAMTS-12 expression. Furthermore, GEP levels were significantly elevated in patients with either osteoarthritis or rheumatoid arthritis. CONCLUSION: Our observations demonstrate a novel protein-protein interaction network between GEP, ADAMTS-7/ADAMTS-12, and COMP. Furthermore, GEP is a novel specific inhibitor of ADAMTS-7/ADAMTS-12-mediated COMP degradation and may play a significant role in preventing the destruction of joint cartilage in arthritis.

The role of ADAMTSs in arthritis.

The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family consists of 19 proteases. These enzymes are known to play important roles in development, angiogenesis and coagulation; dysregulation and mutation of these enzymes have been implicated in many disease processes, such as inflammation, cancer, arthritis and atherosclerosis. This review briefly summarizes the structural organization and functional roles of ADAMTSs in normal and pathological conditions, focusing on members that are known to be involved in the degradation of extracellular matrix and loss of cartilage in arthritis, including the aggrecanases (ADAMTS-4 and ADAMTS-5), ADAMTS-7 and ADAMTS-12, the latter two are associated with cartilage oligomeric matrix protein (COMP), a component of the cartilage extracellular matrix (ECM). We will discuss the expression pattern and the regulation of these metalloproteinases at multiple levels, including their interaction with substrates, induction by pro-inflammatory cytokines, protein processing, inhibition (e.g., TIMP-3, alpha-2-macroglobulin, GEP), and activation (e.g., syndecan-4, PACE-4).

The emerging roles of ADAMTS-7 and ADAMTS-12 matrix metalloproteinases.

The a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) comprise a family of secreted zinc metalloproteinases with a precisely ordered modular organization. These enzymes play an important role in the turnover of extracellular matrix proteins in various tissues and their dysregulation has been implicated in disease-related processes such as arthritis, atherosclerosis, cancer, and inflammation. ADAMTS-7 and ADAMTS-12 share a similar domain organization to each other and form a subgroup within the ADAMTS family. Emerging evidence suggests that ADAMTS-7 and ADAMTS-12 may play an important role in the development and pathogenesis of various kinds of diseases. In this review, we summarize what is currently known about the roles of these two metalloproteinases, with a special focus on their involvement in chondrogenesis, endochondral ossification, and the pathogenesis of arthritis, atherosclerosis, and cancer. The future study of ADAMTS-7 and ADAMTS-12, as well as the molecules with which they interact, will help us to better understand a variety of human diseases from both a biological and therapeutic standpoint.

Natural transformation of helicobacter pylori involves the integration of short DNA fragments interrupted by gaps of variable size.

Helicobacter pylori are gram-negative bacteria notable for their high level of genetic diversity and plasticity, features that may play a key role in the organism's ability to colonize the human stomach. Homeologous natural transformation, a key contributor to genomic diversification, has been well-described for H. pylori. To examine the mechanisms involved, we performed restriction analysis and sequencing of recombination products to characterize the length, fragmentation, and position of DNA imported via natural transformation. Our analysis revealed DNA imports of small size (1,300 bp, 95% confidence limits 950-1850 bp) with instances of substantial asymmetry in relation to selectable antibiotic-resistance markers. We also observed clustering of imported DNA endpoints, suggesting a possible role for restriction endonucleases in limiting recombination length. Additionally, we observed gaps in integrated DNA and found evidence suggesting that these gaps are the result of two or more separate strand invasions. Taken together, these observations support a system of highly efficient short-fragment recombination involving multiple recombination events within a single locus.

miR-199a, a bone morphogenic protein 2-responsive MicroRNA, regulates chondrogenesis via direct targeting to Smad1.

MicroRNAs (miRNA) are short non-coding RNA molecules that regulate a variety of biological processes. The role of miRNAs in BMP2-mediated biological processes is of considerable interest. A comparative miRNA array led to the isolation of several BMP2-responsive miRNAs. Among them, miR-199a(*) is of particular interest, because it was reported to be specifically expressed in the skeletal system. Here we demonstrate that miR-199a(*) is an early responsive target of BMP2: its level was dramatically reduced at 5 h, quickly increased at 24 h and remained higher thereafter in the course of BMP2-triggered chondrogenesis of a micromass culture of pluripotent C3H10T1/2 stem cells. miR-199a(*) significantly inhibited early chondrogenesis, as revealed by the reduced expression of early marker genes for chondrogenesis such as cartilage oligomeric matrix protein (COMP), type II collagen, and Sox9, whereas anti-miR-199a(*) increased the expression of these chondrogenic marker genes. A computer-based prediction algorithm led to the identification of Smad1, a well established downstream molecule of BMP-2 signaling, as a putative target of miR-199a(*). The pattern of Smad1 mRNA expression exhibited the mirror opposite of miR-199a(*) expression following BMP-2 induction. Furthermore, miR-199a(*) demonstrated remarkable inhibition of both endogenous Smad1 as well as a reporter construct bearing the 3-untranslated region of Smad1 mRNA. In addition, mutation of miR-199a(*) binding sites in the 3'-untranslated region of Smad1 mRNA abolished miR-199a(*)-mediated repression of reporter gene activity. Mechanism studies revealed that miR-199a(*) inhibits Smad1/Smad4-mediated transactivation of target genes, and that overexpression of Smad1 completely corrects miR-199a(*)-mediated repression of early chondrogenesis. Taken together, miR-199a(*) is the first BMP2 responsive microRNA found to adversely regulate early chondrocyte differentiation via direct targeting of the Smad1 transcription factor.

Plastic cells and populations: DNA substrate characteristics in Helicobacter pylori transformation define a flexible but conservative system for genomic variation.

Helicobacter pylori, bacteria that colonize the human gastric mucosa, are naturally competent for transformation by exogenous DNA, and show a panmictic population structure. To understand the mechanisms involved in its horizontal gene transfer, we sought to define the interval required from exposure to substrate DNA until DNA uptake and expression of a selectable phenotype, as well as the relationship of transforming fragment length, concentration, homology, symmetry, and strandedness, to the transformation frequency. We provide evidence that natural transformation in H. pylori differs in efficiency among wild-type strains but is saturable and varies with substrate DNA length, symmetry, strandedness, and species origin. We show that H. pylori cells can be transformed within one minute of contact with DNA, by DNA fragments as small as 50 bp, and as few as 5 bp on one flank of a selectable single nucleotide mutation is sufficient substrate for recombination of a transforming fragment, and that double-stranded DNA is the preferred (1000-fold >single-stranded) substrate. The high efficiency of double-stranded DNA as transformation substrate, in conjunction with strain-specific restriction endonucleases suggests a model of short-fragment recombination favoring closest relatives, consistent with the observed H. pylori population biology.