Cartilage oligomeric matrix protein enhances osteogenesis by directly binding and activating bone morphogenetic protein-2.

Bone morphogenetic proteins (BMPs) are effective for bone regeneration, and are used clinically. However, supraphysiological doses are required, which limits their use. Cartilage oligomeric matrix protein is an extracellular matrix protein, which we have previously shown can bind to growth factors of the TGFs family, suggesting that COMP may also bind to BMP-2. Rather than being a passive component of the matrix, COMP may serve as an "instructive matrix" component capable of increasing local growth factor concentration, slowing the diffusion of growth factors, and promoting their biological activity. The purpose of this investigation was to determine whether COMP binds to BMP-2, and whether it promotes the biological activity of BMP-2 with respect to osteogenesis. We found that COMP binds BMP-2, and characterized the biochemical nature of the binding interaction. COMP binding enhanced BMP-2-induced intracellular signaling through Smad proteins, increased the levels of BMP receptors, and up-regulated the luciferase activity from a BMP-2-responsive reporter construct. COMP binding enhanced BMP-2-dependent osteogenesis in vitro, in the C2C12 cell line and in primary human bone mesenchymal stem cells, as measured by alkaline phosphatase activity, matrix mineralization, and gene expression. Finally, we found that COMP enhanced BMP-2-dependent ectopic bone formation in a rat model assessed histologically, by alkaline phosphatase activity, gene expression, and micro-CT. In summary, this study demonstrates that COMP enhances the osteogenic activity of BMP-2, both in-vitro and in-vivo.

Diagnosis of periprosthetic joint infections of the hip and knee.

No preferred test for diagnosis of periprosthetic joint infection exists, and the algorithm for the workup of patients suspected of infection remains unclear. The work group evaluated the available literature to determine the role of each diagnostic modality and devise a practical algorithm that allows physicians to reach diagnosis of periprosthetic joint infection. Ten of the 15 recommendations have strong or moderate evidence in support. These include matters involving erythrocyte sedimentation rate and C-reactive protein level testing, knee and hip aspiration, and stopping the use of antibiotics prior to obtaining intra-articular cultures. The group recommends against the use of intraoperative Gram stain but does recommend the use of frozen sections of peri-implant tissues in reoperation patients in whom infection has not been established, as well as multiple cultures in reoperation patients being assessed for infection. The group recommends against initiating antibiotic treatment in patients with suspected infection until after joint cultures have been obtained, but recommends that prophylactic preoperative antibiotics not be withheld in patients at lower probability for infection.

Estrogen and osteoarthritis.

In menopausal women and the elderly, populations most often affected by osteoarthritis (OA), estrogen levels are lower than normal, which suggests that estrogen may be an important regulator of OA. Estrogen can influence chondrocyte function on multiple levels by interacting with cellular growth factors, adhesion molecules, and cytokines. Nevertheless, findings regarding a correlation between estrogen and OA are inconsistent and inconclusive and range from estrogen protecting against OA to cartilage damage mediated by high levels of estrogen and higher binding to estrogen receptors. In this review, we summarize current in vivo and in vitro research and discuss future directions for analyses of the role of estrogen in OA.

Recent advances toward the clinical application of bone morphogenetic proteins in bone and cartilage repair.

Inefficient healing of bony and cartilaginous defects is a common situation encountered by orthopedic surgeons. Enhancing the regenerative potential of bone and articular cartilage has the potential for profound applications in treatment of nonunions, large segmental bone and cartilage defects, and arthritis. The bone morphogenetic proteins (BMPs) encode a highly conserved class of signaling factors that possess the ability to induce ectopic cartilage and bone formation in vivo. Bone morphogenetic protein family members are expressed during limb development, endochondral ossification, and early fracture and cartilage repair. Loss-of-function and gain-of-function studies have demonstrated the necessity and sufficiency of these genes, respectively, in regulating both cartilage and bone development. Several recent animal studies have demonstrated the potential of BMPs to enhance spinal fusion, repair critical-size defects, accelerate union, and heal articular cartilage lesions. A limited number of clinical trials using BMPs in human beings have been reported, and these agents are currently available for clinical use within and outside the United States. Current challenges to be met are the development of efficient delivery systems to present BMP proteins or genes to target sites and to enhance their duration and function at these locations.

[Effects of bone morphogenetic protein-2 on cartilage oligomeric matrix protein expression in chondrocytes].

OBJECTIVE: To quantitatively evaluate the effects of BMP-2 on the COMP gene expression in both primary human chondrocytes and chondrogenic cell line ATDC55. METHODS: Human adult and fetal chondrocytes were stimulated by BMP-2. The COMP gene expression level was analyzed by real time reverse transcription-PCR assay and normalized to a reference mRNA (GAPDH). Next, a full-length mCOMP promoter cloned upstream of luciferase reporter gene was transfected into ATDC55 cells and stimulated by 500 micrograms.L-1 BMP-2 in the presence or absence of 10 micrograms.L-1 of Noggin. RESULTS: We found that BMP-2 up-regulated COMP gene expression by approximate 3 folds in human adult chondrocytes, and 1.5 folds in human fetal chondrocytes. The difference in magnitude of COMP gene stimulation by BMP-2 might attribute to the difference of COMP gene basal expression level in chondrocytes from different sources because it was found that the COMP gene expression was 2 folds higher in quiescent fetal chondrocytes than in adult chondrocytes. For further analysis of the effect of BMP-2 on COMP gene expression by RT-PCR, a rat chondrogenic cell line of ATDC55 cells was used. While no COMP gene expression was detected in unstimulated cells, COMP expression was significantly induced after treatment with BMP-2. This induction could be specifically blocked by 10 micrograms.L-1 of Noggin. It was found that BMP-2 markedly increased the luciferase reporter activity by about 5 folds and again, Noggin specifically blocked the BMP-2 activity. CONCLUSION: BMP-2 up-regulates the COMP gene expression in both primary human chondrocytes and chondrogenic cell line ATDC55.

Instability following total hip arthroplasty.

Dislocation is the second most common complication of total hip arthroplasty. Most dislocations occur early in the postoperative period and are caused by patient factors, surgical factors, or a combination of both. Patient factors that predispose to postoperative dislocation include previous surgery and neurologic impairment. Surgical factors include surgical approach, component orientation, and prosthetic and/or bony impingement. Evaluation of patients undergoing total hip arthroplasty requires a thorough history and physical examination, as well as a detailed radiographic assessment. Closed treatment of instability is successful in two thirds of cases; the remainder require surgical management. Surgical techniques used to treat or minimize risk of further dislocation include revision arthroplasty, trochanteric advancement, use of elevated rim liners, and use of constrained liners.

Duplex ultrasonography in patients suspected of postoperative pulmonary embolism following total joint arthroplasty.

Duplex ultrasonography of the deep venous system of the lower extremities is often utilized in the diagnostic evaluation of total hip and knee arthroplasty patients suspected of pulmonary embolism in an attempt to identify the embolic source. A retrospective review of 135 patients who were clinically suspected of pulmonary embolism after 71 total knee arthroplasties and 64 total hip arthroplasties was performed. Of the 35 patients diagnosed with pulmonary embolism, 2 (5.7%) had deep venous thrombosis identified by duplex ultrasonography. The routine use of this imaging modality is not an effective strategy for identifying clinically significant deep venous thrombosis that leads to pulmonary embolism. A negative duplex ultrasound result should not preclude an extensive evaluation for pulmonary thrombosis in symptomatic patients.

Revision of polyethylene acetabular liners with a cemented polyethylene cup: a laboratory study.

Various technique parameters for the revision of failed polyethylene acetabular liners using a cemented polyethylene cup were evaluated in this laboratory study. The effects of cement mantle thickness and roughening the inner surface of the shell or outer surface of the cup were determined by measuring cup dissociation strength from the metal shell after cyclic loading of the cup. The use of a cement mantle thickness of 2 to 4 mm provided dissociation strengths 3 to 4 times greater than that of the original, press-fit polyethylene liner. If a failed acetabular liner is revised by a cemented cup within the existing, well-fixed, metal shell, the size of the cup selected should create a cement mantle of <4 mm. Roughening the inside of a smooth shell or one with few screw-holes increases fixation strength approximately 20% but also creates particulate debris.