Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the proteinase K subfamily of subtilases that reduces the number of LDL receptors (LDLRs) in liver through an undefined posttranscriptional mechanism. We show that purified PCSK9 added to the medium of HepG2 cells reduces the number of cellsurface LDLRs in a dose-and time-dependent manner. This activity was approximately 10-fold greater for a gain-of-function mutant, PCSK9(D374Y), that causes hypercholesterolemia. Binding and uptake of PCSK9 were largely dependent on the presence of LDLRs. Coimmunoprecipitation and ligand blotting studies indicated that PCSK9 and LDLR directly associate; both proteins colocalized to late endocytic compartments. Purified PCSK9 had no effect on cell-surface LDLRs in hepatocytes lacking autosomal recessive hypercholesterolemia (ARH), an adaptor protein required for endocytosis of the receptor. Transgenic mice overexpressing human PCSK9 in liver secreted large amounts of the protein into plasma, which increased plasma LDL cholesterol concentrations to levels similar to those of LDLR-knockout mice. To determine whether PCSK9 was active in plasma, transgenic PCSK9 mice were parabiosed with wild-type littermates. After parabiosis, secreted PCSK9 was transferred to the circulation of wild-type mice and reduced the number of hepatic LDLRs to nearly undetectable levels. We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels.

Femoroacetabular impingement (FAI) is considered a cause of labrochondral disease and secondary osteoarthritis. Nevertheless, the clinical syndrome associated with FAI is not fully characterized. We determined the clinical history, functional status, activity status, and physical examination findings that characterize FAI. We prospectively evaluated 51 patients (52 hips) with symptomatic FAI. Evaluation of the clinical history, physical exam, and previous treatments was performed. Patients completed demographic and validated hip questionnaires (Baecke et al., SF-12, Modified Harris hip, and UCLA activity score). The average patient age was 35 years and 57% were male. Symptom onset was commonly insidious (65%) and activity-related. Pain occurred predominantly in the groin (83%). The mean time from symptom onset to definitive diagnosis was 3.1 years. Patients were evaluated by an average 4.2 healthcare providers prior to diagnosis and inaccurate diagnoses were common. Thirteen percent had unsuccessful surgery at another anatomic site. On exam, 88% of the hips were painful with the anterior impingement test. Hip flexion and internal rotation in flexion were limited to an average 97°and 9°, respectively. The patients were relatively active, yet demonstrated restrictions of function and overall health. These data may facilitate diagnosis of this disorder.

Diagnostic Level IV. See Instructions to Authors for a complete description of levels of evidence.

Objective To describe outcomes of the conservative treatment of patients who had the clinical presentation of a prearthritic, intra-articular hip disorder, including acetabular labral tears, developmental hip dysplasia, and femoroacetabular impingement. Design Prospective observational clinical outcomes study. Setting Outpatient orthopedic clinic at a tertiary university hospital. Patients Patients presenting with prearthritic, intra-articular hip disorders were recruited. Fifty-eight consecutive patients were enrolled; 6 were lost to follow-up, and 52 subjects completed the study. Methods Patients were recruited on the basis of symptoms, distribution of pain, and the findings of a physical examination. Radiographic measurements of the hip were obtained for all subjects to describe the presence or absence and extent of deformity and/or osteoarthritis. All subjects completed a directed course of conservative treatment. After 3 months of conservative care, subjects with continued limitations, reduction of symptoms with a diagnostic intra-articular hip injection, and a surgically amenable lesion found on a magnetic resonance arthrogram proceeded to surgery. Main Outcome Measurements Numeric Pain Score (0–10), Short Form-12, Modified Harris Hip Score, Western Ontario and McMaster Universities Osteoarthritis Index, Nonarthritic Hip Score, Baecke Questionnaire of Habitual Activity, and patient choice to have surgery. Results Fifty-eight patients (9 men and 49 women) with a mean age of 35 ± 11 years (range, 18–50 years) enrolled in the study. Fifty-two subjects completed the study. Twenty-three subjects (44%) reported satisfaction with conservative care. Twenty-nine subjects (56%) chose to have surgery. Both groups demonstrated equally significant improvement (P value ranges: P = .03 to P = .0001) in all outcome measures from baseline to 1-year follow-up. Subjects who chose surgery had higher baseline activity scores compared with the conservative treatment group (P = .02). Conclusion All subjects with signs and symptoms of prearthritic, intra-articular hip disorders who were treated with conservative treatment alone and with conservative treatment followed by surgery demonstrated significant improvement in pain and functioning from baseline to 1 year. Forty-four percent of patients improved with conservative care alone, and 56% chose to have surgery after receiving conservative care. Persons with more active lifestyles were more likely to choose surgery. These data suggest that a trial of conservative management for persons with prearthritic, intra-articular hip disorders should be considered before engaging in surgical intervention.

Background: Acetabular dysplasia is recognized as a cause of early degenerative hip osteoarthritis. The purpose of this