title: Characterization of osteoarthritic human knees indicates potential sex differences.
abstract: BACKGROUND
  The prevalence of osteoarthritis is higher in women than in men in every age group, and overall prevalence increases with advancing age. Sex-specific differences in the properties of osteoarthritic joint tissues may permit the development of sex-specific therapies. Sex hormones regulate cartilage and bone development and homeostasis in a sex-dependent manner. Recent in vitro studies show that the vitamin D3 metabolite 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] also has sex-specific effects on musculoskeletal cells, suggesting that vitamin D3 metabolites may play a role in osteoarthritis-related sex-specific differences. The purpose of this study was to determine if sex-specific differences exist in synovial fluid and knee tissues isolated from male and female patients with severe knee osteoarthritis. We determined the presence of vitamin D3 metabolites, inflammatory cytokines, growth factors, and matrix metalloproteinases (MMPs) in synovial fluid and assessed responses of articular chondrocytes and subchondral osteoblasts to 17β-estradiol, dihydrotestosterone, and 1α,25(OH)2D3.
  
  
  METHODS
  Samples from knee joints of 10 Caucasian male and 10 Caucasian female patients with advanced osteoarthritis aged 65 to 75 years were obtained from total knee arthroplasty. Vitamin D metabolites, cytokines, MMPs, and growth factors in the synovial fluid were measured. Primary cultures of chondrocytes were isolated from fibrillated articular cartilage adjacent to osteoarthritis lesions and minimally affected cartilage distal to the lesion. Osteoblasts were isolated from the subchondral bone. Expression of receptors for 17β-estradiol and 1α,25(OH)2D3 was assessed by real-time PCR. Chondrocytes and osteoblasts were treated with 10(-8) M 17β-estradiol, dihydrotestosterone, or 1α,25(OH)2D3 and effects on gene expression and protein synthesis determined.
  
  
  RESULTS
  Histology of the articular cartilage confirmed advanced osteoarthritis. Sex differences were found in synovial fluid levels of vitamin D metabolites, cytokines, and metalloproteinases as well as in the cellular expression of receptors for 17β-estradiol and 1α,25(OH)2D3. Male cells were more responsive to 1α,25(OH)2D3 and dihydrotestosterone, whereas 17β-estradiol-affected female cells.
  
  
  CONCLUSIONS
  These results demonstrate that there are underlying sex differences in knee tissues affected by osteoarthritis. Our findings do not address osteoarthritis etiology but have implications for different prevention methods and treatments for men and women. Further research is needed to better understand these sex-based differences.
authors.affiliation: Department of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA USA.
authors.forename: Qingfen
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Center for Musculoskeletal Care, Yale University School of Medicine, New Haven, CT USA.
authors.forename: Mary I
authors.initials: MI
authors.lastname: O'Connor
authors.affiliation: Department of Orthopaedics, University of California at San Diego, San Diego, CA USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Coutts
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA USA.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Hyzy
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Olivares-Navarrete
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA USA ; Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX USA.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Schwartz
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA USA ; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA USA ; School of Engineering, Virginia Commonwealth University, 601 West Main Street, Suite 331, Richmond, VA 23284 USA.
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Boyan
keywords: 1α,25(OH)2D3; 24R,25(OH)2D3; Chondrocytes; Dihydrotestosterone; Estrogen; Osteoarthritis; Osteoblasts; Testosterone; Vitamin D