Hormonal modulation of connective tissue homeostasis and sex differences in risk for osteoarthritis of the knee

Abstract

Young female athletes experience a higher incidence of ligament injuries than their male counterparts, females experience a higher incidence of joint hypermobility syndrome (a risk factor for osteoarthritis development), and post-menopausal females experience a higher prevalence of osteoarthritis than age-matched males. These observations indicate that fluctuating sex hormone levels in young females and loss of ovarian sex hormone production due to menopause likely contribute to observed sex differences in knee joint function and risk for loss of function. In studies of osteoarthritis, however, there is a general lack of appreciation for the heterogeneity of hormonal control in both women and men. Progress in this field is limited by the relatively few preclinical osteoarthritis models, and that most of the work with established models uses only male animals. To elucidate sex differences in osteoarthritis, it is important to examine sex hormone mechanisms in cells from knee tissues and the sexual dimorphism in the role of inflammation at the cell, tissue, and organ levels. There is a need to determine if the risk for loss of knee function and integrity in females is restricted to only the knee or if sex-specific changes in other tissues play a role. This paper discusses these gaps in knowledge and suggests remedies.

Figure 1

Synthesis of sex steroids (http://en.wikipedia.org/wiki/File:Steroidogenesis.svg#file). The schematic indicates the various enzymatic pathways for synthesis of different biologically active steroid metabolites of cholesterol as the starting molecule. The various pathways are regulated in different tissues by the expression of specific enzymes that catalyze the metabolic conversions in mitochondria and smooth endoplasmic reticulum. Some tissues (e.g., adrenal glands, gonadal tissues) are the primary source of some of the biologically active steroid metabolites, whereas others can be made locally in tissues such as articular cartilage when appropriately stimulated.

Figure 2

Variable response of male human articular chondrocytes to 17β-estradiol. Chondrocytes were isolated from three male donors (<30 years) with no evidence of OA. Confluent cultures of second-passage cultures were treated with 10^-8 to 10^-10 M 17β-estradiol for 24 hours and proteoglycan production was measured as a function of ³⁵S-sulfate incorporation into sulfated glycosaminoglycans, a hallmark of cartilage extracellular matrix. Data are means ± SEM, N = 6 independent cultures per variable. *p < 0.05, treatment v. control. Cells from two of the donors exhibited no response to the hormone in two different sets of experiments, whereas cells from one of the donors were responsive to the hormone. Data are provided courtesy of Ramsey Kinney, MD, PhD, Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA.