CAMKK2 is upregulated in primary human osteoarthritis and its inhibition protects against chondrocyte apoptosis.

OBJECTIVE: To investigate the role of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) in human osteoarthritis. MATERIALS AND METHODS: Paired osteochondral plugs and articular chondrocytes were isolated from the relatively healthier (intact) and damaged portions of human femoral heads collected from patients undergoing total hip arthroplasty for primary osteoarthritis (OA). Cartilage from femoral plugs were either flash frozen for gene expression analysis or histology and immunohistochemistry. Chondrocyte apoptosis in the presence or absence of CAMKK2 inhibition was measured using flow cytometry. CAMKK2 overexpression and knockdown in articular chondrocytes were achieved via Lentivirus- and siRNA-mediated approaches respectively, and their effect on pro-apoptotic and cartilage catabolic mechanisms was assessed by immunoblotting. RESULTS: CAMKK2 mRNA and protein levels were elevated in articular chondrocytes from human OA cartilage compared to paired healthier intact samples. This increase was associated with elevated catabolic marker matrix metalloproteinase 13 (MMP-13), and diminished anabolic markers aggrecan (ACAN) and type II collagen (COL2A1) levels. OA chondrocytes displayed enhanced apoptosis, which was suppressed following pharmacological inhibition of CAMKK2. Levels of MMP13, pSTAT3, and the pro-apoptotic marker BAX became elevated when CAMKK2, but not its kinase-defective mutant was overexpressed, whereas knockdown of the kinase decreased the levels of these proteins. CONCLUSIONS: CAMKK2 is upregulated in human OA cartilage and is associated with elevated levels of pro-apoptotic and catabolic proteins. Inhibition or knockdown of CAMKK2 led to decreased chondrocyte apoptosis and catabolic protein levels, whereas its overexpression elevated them. CAMKK2 may be a therapeutic target to prevent or mitigate human OA.

Intramedullary Nailing of Lower-Extremity Periarticular Fractures.

Intramedullary nailing is used to stabilize distal femoral, proximal tibial, and distal tibial periarticular fractures with short proximal or distal segments, as well as some intra-articular fractures in which a stable articular block can be created. Intramedullary nailing may be beneficial in complex fracture patterns with diaphyseal extension, segmental injuries, or patients who might benefit from a decreased incision burden. Step 1: Preoperative planning. Review imaging and make sure there is a nail with adequate interlocks. Consider the use of adjunctive techniques to obtain and maintain alignment, and how intra-articular fracture lines will be stabilized. Step 2: Position and prepare the patient. Step 3: Exposure for nailing via suprapatellar, infrapatellar, or knee arthrotomy approaches. Limited exposure of fracture planes may also be necessary for adjunctive techniques. Step 4: Convert an OTA/AO C-type fracture to an A-type fracture if needed. Step 5: Obtain appropriate starting point and trajectory with the nail starting wire and use the opening reamer. Step 6: Obtain reduction, if not yet done, and pass the ball-tipped reaming wire across the fracture. Step 7: Ream while holding reduction. Step 8: Pass nail. Step 9: Verify reduction is maintained and correct if needed. Step 10: Place interlocks, preferably multiplanar, in the short segment. Create a fixed angle construct if desired and convert adjunctive techniques/provisional fixation to definitive fixation as needed. Step 11: Perform final checks. Step 12: Closure. Step 13: Postoperative plan. For extra-articular fractures, one may expect healing with maintained alignment from what was present at the case end intraoperatively in the vast majority of cases. For intra-articular fractures, development of posttraumatic arthritis is an additional concern.

Conversion of external fixation to open reduction and internal fixation for complex distal radius fractures.

INTRODUCTION: Distal radius fractures are common injuries treated in a multitude of ways. One treatment paradigm not extensively studied is initial treatment by external fixation (EF) followed by conversion to open reduction internal fixation (ORIF). Such a paradigm may be beneficial in damage control situations, when there is extensive soft tissue injury, or when appropriate personnel/hospital resources are not available for immediate internal fixation. HYPOTHESIS: There is no increased risk of infection when converting EF to ORIF in the treatment of complex distal radius fractures when conversion occurs early or if EF pin sites are overlapped by the definitive fixation. MATERIALS AND METHODS: Using an IRB approved protocol, medical records over nine years were queried to identify patients with distal radius fractures that had undergone initial EF and were later converted to ORIF. Charts were reviewed for demographic data, injury characteristics, operative details, time to conversion from EF to ORIF, assessment of whether the EF pin sites overlapped the definitive fixation, presence of infection after ORIF, complications, and occupational therapy measurements of range of motion and strength. RESULTS: In total, 16 patients were identified, only one of which developed an infection following conversion to ORIF. Fisher's exact testing showed that infection did not depend on open fracture, time to conversion of one week or less, presence of EF pin sites overlapping definitive fixation, fracture classification, high energy mechanism of injury, or concomitant injury to the DRUJ. DISCUSSION: Planned staged conversion from EF to ORIF for complex distal radius fractures does not appear to result in an increased rate of infection if conversion occurs early or if the EF pin sites are overlapped by definitive fixation. This treatment paradigm may be reasonable for treating complex distal radius fractures in damage control situations, when there is extensive soft tissue injury, or when appropriate personnel/hospital resources are not available for immediate internal fixation. LEVEL OF EVIDENCE: IV, retrospective case series.