Identification of miRNAs Associated With Gender Difference in Osteoarthritis Patients

Osteoarthritis (OA) is a chronic degenerative joint disease of considerable socio-economic impact, of which a primary and a secondary form are distinguished. Primary OA is a mild form that occurs mainly in the joints of the hands, feet, knee, and hip, and appears in young subjects. Secondary OA derives from different factors that modify the microenvironment of the cartilage such as trauma, congenital joint deformities, metabolic defects, infections that cause post-infectious arthritis, endocrine and neuropathic diseases and disorders that alter the normal structure and function of hyaline cartilage (eg . rheumatoid arthritis, gout, chondrocalcinosis), and is more prevalent in old age.

As regards the secondary form of OA, correlated with advancing age due to the natural aging process of the joint and to events of a traumatic nature, it is hypothesized that a key role in the etiology and progression of the disease may be played by the genre. Immune responses are known to differ in males and females. Some meta-analyzes reveal how the presence of some polymorphisms (ADAM12) in male patients predispose to the development of OA more than in women, especially in the knee joint. Furthermore, new molecular evidence suggests that in patients with OA there is a gender-specific activation of PI3K-AKT and hypoxia signaling, suggesting the presence of possible gender-specific protein factors that may modulate bone metabolism and disease progression. In this regard, studies evaluating the responses of joint chondrocytes to systemic factors suggest that there are differences in the biochemical and molecular characteristics of male and female cells, without prejudice to the fundamental role of hormones in the different gender-specific response to the development and progression of pathology.

It is widely known that the regulation of bone remodeling processes is entrusted to a hormonal mechanism, which mainly involves parathyroid hormone, vitamin D and calcitonin. Other hormone regulators involved are sex hormones (estrogen, testosterone), thyroid hormones, corticosteroids (including cortisone), insulin, and growth factors (including growth hormone).

In the development of OA it is thought that sex hormones may act in a prevalent way. In women of childbearing age, estrogen has a protective action on the bone, inhibiting bone remodeling, especially bone resorption; while in the post-menopausal period, circulating estrogens are reduced compared to testosterone, strongly contributing to an imbalance in bone remodeling, favoring the stiffening of the subchondral bone and the development of osteophytes at the joint margins. The osteophytes seem to be developed in an attempt to stabilize the joint damage. Consequently, the synovial membrane becomes inflamed and thickened, producing synovial fluid with less viscosity and in greater quantities and favoring the development of an inflammatory process on site. Obviously, the entire joint will be damaged up to the reduction of joint mobility and ankylosis.

Similarly men, even if they do not undergo a real andropause, starting from 45 years of age they suffer a progressive decline in the production and release of testosterone, whose levels after the age of 65 are no longer sufficient to maintain good efficiency of the bone tissue favoring its resorption and the possible onset of the pathology. However, it is not known whether the potential differences related to gender, in terms of hormonal release and alteration of bone homeostasis, may be related to the severity of the disease, that is to the development of the inflammatory condition associated with it.