Marco Lenzi e Luca Tarducci
Definition of Osteoarthritis
A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans.
Osteoarthritis (OA) is the most common joint disorder in the world. In Western populations it is one of the most frequent causes of pain, loss of function and disability in adults. Radiographic evidence of OA occurs in the majority of people by 65 years of age, although only 60% of those will have symptoms. In the US it is second only to ischaemic heart disease as a cause of work disability in men over 50 years of age. Men under age 55 are more likely to have OA than women in the same age range. After age 55, however, women are more commonly affected. Overall, more women have osteoarthritis than men.
Osteoarthritis: epidemiology. 2006
The main symptom is pain, causing loss of ability and often stiffness. OA can cause a crackling noise (called crepitus) when the affected joint is moved or touched and people may experience muscle spasms and contractions in the tendons. The affected joints usually feel better with gentle use but worse with excessive or prolonged use, thus distinguishing it from rheumatoid arthritis.
In smaller joints, such as at the fingers, hard bony enlargements may form, and though they are not necessarily painful, they do limit the movement of the fingers significantly. OA at the toes leads to the formation of bunions, rendering them red or swollen.
There is no single sign, symptom, or test that can diagnose OA. Instead, the diagnosis is based on a consideration of several factors, including:
- characteristic symptoms;
- laboratory tests, to rule out conditions with similar symptoms;
- x-rays, helpful for tracking the status of osteoarthritis over time, but which may appear normal during the early stages;
- other types of imaging tests, such as ultrasound and magnetic resonance imaging (MRI), which may be used to detect damage to cartilage, ligaments, and tendons, which cannot be seen on x-ray.
The pathogenesis is unknown but in the early phase there is a decrease in proteoglycan content, which results in reduction of intercellular water content in the cartilage matrix. This leads to disruption of articular cartilage superficial layer. The degenerative processes can extends to the bone, where the exposed subcondral bone becomes a new articular surface. These changes result in progressive reduction of mobility and pain when the joint is moved.
Sections from the knees of 7-month-old rats subjected to ovariectomy, stained with Toluidine blue, showing the distal femur and proximal tibia (a,b) with the meniscus (M) to the left (a). The surface erosion is indicated by the long, thin black bar (b). Scale bars: 200 μm.
Articular cartilage structure
- Cell 3-5%
- Multiadhesive glycoproteins 5%
- Proteoglycans (aggrecan)
- Collagens 15% :
- 5% III,VI,X,XII,XIV
- 15% IX,XI
- 80% II
- Intercellular water 60-80%
One of the cardinal compound in the cartilage structure is the proteoglycan called aggrecan. It is made of a core protein aggrecan and a GAG, mainly chondroitin sulfate and cherant sulfate. This brush-like structure is itself attached by link proteins to Ialuronic Acid.
Estrogens in OA
It has been shown that OA has a strong correlation with the lowering of estrogen hormone in aging woman.
Estrogens have a direct effect on adult articular cartilage, as they promote chondrocyte homeostasis and protect cartilage from degradation and erosion occurring during menopause.
Functional estrogen receptors are present in articular cartilage, and when estrogens bind to them they modulate the transcription of target genes allowing expression of the specific chondrogenic markers such as proteoglycans and type II collagen or inhibition of catabolic markers such as metalloproteases (aggrecanase) and interleukins.
There are two types of estrogen receptors, ERα and ERβ, which are both espressed in articular tissues. The receptors have four functional domains: a DNA-binding domain (DBD), a ligand-binding domain (LBD) and two transcriptional activation functions (AF-1 and AF-2).
In the canonical pathway ERs act as ligand-activated transcription factors in the nucleus that specifically bind to estrogen response elements (EREs) in the promoters of target genes. The ERE has been described as a palindromic sequence (CAGGTCAnnnTGACCTG) in animal model but also half palindromic elements have shown to be able to mediate estrogen inducibility. Those difference in binding are achieved by means of a side change rearrangement in the DBD which are due to the presence of a different nucleotide. The binding is made possible by the zinc fingers in the DBD; the first zinc finger is capable of binding in a sequence specific manner while the second is involved in dimerization and half site spacing recognition. Often more than one ERE is seen in the regulatory region of a estrogen-target gene, which lead to the concept of an Estrogene Response Unit (ERU). An ERU comprise imperfect palindromic elements or even half elements sometimes separated by hundreds of base pair.
Otherwise ligand-bound ERs interact with other transcriptional factors, such as activator protein (AP)-1, NF-κB and Sp1, exerting their action on different promoters that contain GC boxes. Studies have shown the presence of multiple binding sites for (AP)-1, NF-κB and Sp1 in the 5'untranslated region of aggrecan gene (5'UTR). SP-1 in particular plays a key role in regulating transcription initiation of TATA-less promoters. A conserved TATG repeat may be the equivalent of a TATA box in TATA-less promoters such as the aggrecan promoter. So 5'UTR can stimulate the activity of the human aggrecan promoter in chondrocytes.
ERs are also localized on the cell membrane and they can activate the PI3K/Akt or PKC/MAPK signal transduction pathways.
Finally, ERs can be stimulated by growth factors in the absence of ligands.
Osteoarthritis associated with estrogen deficiency. 2009
Functional estrogen receptors in adult articular cartilage: estrogen replacement therapy increases chondrocyte synthesis of proteoglycans and insulin-like growth factor binding protein 2. 2000
Regulatory activities of the 5'- and 3'-untranslated regions and promoter of the human aggrecan gene.1998
The link between OA and Royal Jelly
As we pointed out earlier one of the main event in OA progression is the loss of proteoglycans replacement. Thus hormone substitution therapy is used to treat the post menopausal OA although it is known that such therapy has many side effect leading, for example, to major incidence of breast cancer. Because of this many woman search for an alternative therapy in the field of traditional medicine including Royal Jelly (RJ).
RJ contains a 7% of lipidis among which there are steroids. This substance are called 10H2DA, 10HDA, 2DEA and 24MET and they have shown to mediate estrogen signaling, by modulating the recruitment of ERα, ERβ and co-activators to target genes.
The antiestrogenic effect in breast cancer cells, the favorable effect on osteoblasts and the lack of effect on endometrial cell viability suggest that these steroids may be potential natural SERMs (selective estrogen receptor modulators).
The biological effects of these steroids have been examined in a concentration range of 10−10 M - 10−5 M, which are physiologically achievable concentrations.
Chemical structures of (A) 10-hydroxy-trans-2-decenoic acid (B) 10-hydroxydecanoic acid © trans-2-decenoic acid and (D) 24-methylenecholesterol.
Therefore RJ used as an alimentary supplement may show some therapeutic effects like pain relief and slowing the progression of OA.
Fatty Acids Derived from Royal Jelly Are Modulators of Estrogen Receptor Functions. 2010