Dysfunction of the median nerve at the elbow or proximal forearm can characterize two distinct clinical entities: pronator syndrome (PS) or anterior interosseous nerve (AIN) syndrome. PS is characterized by vague volar forearm pain, with median nerve paresthesias and minimal motor findings. AIN syndrome is a pure motor palsy of any or all of the muscles innervated by that nerve: the flexor pollicis longus, the flexor digitorum profundus of the index and middle fingers, and the pronator quadratus. The sites of anatomic compression are essentially the same for both disorders. Typically, the findings of electrodiagnostic studies are normal in patients with PS and abnormal in those with AIN syndrome. PS is a controversial diagnosis and is typically treated nonsurgically. AIN syndrome is increasingly thought to be neuritis and it often resolves spontaneously following prolonged observation. Surgical indications for nerve decompression include persistent symptoms for >6 months in patients with PS or for a minimum of 12 months with no signs of motor improvement in those with AIN syndrome.
Recombinant human BMP-2 (rhBMP-2) is a potent osteoinductive agent, but has been associated not only with bone formation, but also osteoclastogenesis and bone resorption. Osteoprotegerin (OPG) is a RANKL inhibitor that blocks differentiation and function of osteoclasts. We hypothesized that the combination of local BMP-2 (recombinant protein or a product of gene therapy) plus systemic OPG-Fc is more effective than BMP-2 alone in promoting bone repair. To test this hypothesis we used a mouse critical-sized femoral defect model. Col2.3eGFP (osteoblastic marker) male mice were treated with rhBMP-2 (group I), rhBMP-2 and systemic OPG (group II), rhBMP-2 and delayed administration of OPG (group III), mouse BM cells transduced with a lentiviral vector containing the BMP-2 gene (LV-BMP-2; group IV), LV-BMP-2 and systemic OPG (group V), a carrier alone (group VI) and administration of OPG alone (group VII). All bone defects treated with BMP-2 (alone or combined with OPG) healed, whereas minimal bone formation was noted in animals treated with the carrier alone or OPG alone. MicroCT analysis showed that bone volume (BV) in rhBMP-2 + OPG and LV-BMP-2 + OPG groups was significantly higher compared to rhBMP-2 alone (p < 0.01) and LV-BMP-2 alone (p < 0.001). Similar results were observed in histomorphometry, with rhBMP-2 alone defects exhibiting significantly lower bone area (B.Ar) compared to rhBMP-2 + OPG defects (p < 0.005) and LV-BMP-2 defects having a significantly lower B.Ar compared to all BMP-2 + OPG treated groups (p ≤ 0.01). TRAP staining demonstrated a major osteoclast response in the groups that did not receive OPG (rhBMP-2, LV-BMP-2 and sponge alone) beginning as early as 7 days post-operatively. In conclusion, we demonstrated that locally delivered BMP-2 (recombinant protein or gene therapy) in combination with systemically administered OPG improved bone healing compared to BMP-2 alone in a mouse critical-sized bone defect. These data indicate that osteoclasts can diminish healing responses to BMP-2 and that RANKL inhibition may thus accentuate BMP-2 efficacy.
The role that transduced mouse bone marrow stromal cells (mBMSCs) engineered to overexpress human bone morphogenetic protein 2 (BMP-2) play in healing critical-sized skeletal defects is largely unknown. We evaluated the interaction between host osteoprogenitor cells and donor mBMSCs transduced with either a lentiviral (LV) vector-expressing red fluorescent protein (RFP) with or without BMP-2 that were implanted into a critical-sized femoral defect. Radiographs taken at the time of killing were evaluated using a five-point scaled scoring system. Frozen histologic sections were analyzed to assess both the transduced cells' role in bone repair and the local osteoprogenitor response. There was complete radiographic bridging in 94% of group I (LV-RFPch-BMP-2-cmyc) and 100% of group III (recombinant human BMP-2) specimens. Radiographs demonstrated a lack of healing in group II (LV-RFPch). Mouse BMSCs transduced with an LV-RFPch-BMP-2 vector were able to induce host cells to differentiate down an osteoblastic lineage and heal a critical-sized defect. However, the donor cells appeared to be functioning as a delivery vehicle of BMP-2 rather than actually differentiating into osteoblasts capable of participating in bone repair as evidenced by a lack of colocalization of the transduced cells to the sites of skeletal repair where the host progenitor cells were found.
Our study demonstrated that combining an osteoinductive agent with a systemically administered antibody that promotes bone formation can enhance bone repair and has potential as a therapeutic regimen in humans.
While the majority of fractures heal normally, it is estimated that ~10% of fractures exhibit some level of delayed or impaired healing. Although radiography is the primary diagnostic tool to assess the progression of fracture healing, radiographic features only qualitatively correlate with tissue level increases in mineral content and do not quantitatively measure underlying biological processes that are associated with the progression of healing. Specific metaloproteinases have been shown to be essential to processes of both angiogenesis and mineralized cartilage resorption and bone remodeling at different phases of fracture healing. The aim of this study was to determine the potential of using a simple urine based assay of the activity of two MMPs as a means of assessing the biological progression of fracture healing through the endochondral phase of healing. Using a standard mid-diaphyseal murine model of femoral fracture, MMP9 and MMP13 proteins and enzymatic activity levels were quantified in the urine of mice across the time-course of fracture healing and compared to the mRNA and protein expression profiles in the calluses. Both urinary MMP9 and MMP13 protein and enzymatic activity levels, assessed by Western blot, zymogram and specific MMP fluorometric substrate assays, corresponded to mRNA expression and immunohistologic assays of the proteins within callus tissues. These studies suggest that urinary levels of MMP9 and MMP13 may have potential as metabolic markers to monitor the progression of fracture healing.
Orthopaedic surgeons continue to search for cost-effective bone graft substitutes to enhance bone repair. Teriparatide (PTH 1-34) and demineralized bone matrix (DBM) have been used in patients to promote bone healing. We evaluated the efficacy of PTH and DBM in healing a critical sized femoral defect in three lineage-specific transgenic mice expressing Col3.6GFPtopaz (preosteoblastic marker), Col2.3GFPemerald (osteoblastic marker) and a-SMA-Cherry (pericyte/myofibroblast marker). Mid-diaphyseal defects measuring 2 mm in length were created in the central 1/3 of mice femora using a circular saw and stabilized with an alveolar distractor device and cerclage wires. Three groups were evaluated: Group I, PTH 30 mg/kg injection daily, Group II, PTH 30 mg/kg injection daily þ DBM, and Group III, DBM þ 30mL saline injection. PTH was given for 28 days or until the time of sacrifice. Animals were sacrificed at 7, 14, 28, and 56 days. Radiographs at the time of sacrifice were evaluated using a 5-point scaled scoring system. Radiographs showed a lack of healing across all treatment groups at all time points: Group I, 1.57 þ/À 0.68; Group II, 3.00 þ/À 1.29; and Group III, 2.90 þ/À 1.03. Bone formation in the defect as measured by radiographic healing score was significantly better at 56 days in Groups II (p ¼ 0.01) and III (p < 0.01) compared to Group I. Across all treatment groups and time points the defects were largely absent of osteoprogenitor cells based on gross observation of frozen histology and quantitation of cellular based histomorphometric parameters. Quantitation of frozen histologic slides showed a limited osteoprogenitor response to PTH and DBM. Our results suggest that the anabolic agent teriparatide is unable to induce healing in a critical sized mouse femoral defect when given alone or in combination with the DBM preparation we used as a local bone graft substitute.
Background: The subscapularis tendon is commonly released during shoulder arthroplasty, and its integrity and repair postoperatively have been shown important to help maximize patient function. However, diagnosing subscapular tendon failure can be difficult with magnetic resonance imaging secondary to metal artifact as well as very costly. Purpose: The purpose of this study was to assess the utility of ultrasound imaging in evaluating subscapularis integrity at specific time points following shoulder arthroplasty, in a blinded fashion. Secondarily, we report on the correlation between the condition of the subscapularis and quality-of-life outcome measures. Study Design: Prospective case series. Methods: Ultrasounds were completed preoperatively and postoperatively at 1 week as well as at 1, 3, and 6 months. Each was read by a single musculoskeletal radiologist and categorized as "intact," "torn," or "unclear." Clinical outcome was evaluated using the Western Ontario Osteoarthritis Shoulder (WOOS) index at these same time points. Results: The final study group consisted of 35 procedures in 33 patients (19 females and 14 males, mean age 66 AE 9 years). Three patients had postoperative subscapularis failures that were confirmed in the operating room at the time of repair. Of 24 sonographs categorized as "unclear" in the postoperative period, the majority (n ¼ 12, 50%) were taken at 1 week. Compared to preoperative scores, patients had lower WOOS scores at 1, 3, and 6 months postoperatively (P <.001). Correlation analysis did not reveal an association between the ultrasound readings and the WOOS scores postoperatively. Conclusion: The utility of ultrasound examination of the subscapularis tendon following shoulder arthroplasty is limited by timing and may be most useful when used by the physician within clinical context. Significant improvement was noted in disease-specific quality-of-life scores regardless of the status of the subscapularis tendon as read on ultrasound.
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