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Pathophysiology and Etiology of Osteoarthritis
Izabel Cristina Custodio de Souza*
Izabel Cristina Custodio de Souza, Federal University of Pelotas, Department of
Morphology
*
Corresponding author: Izabel Cristina Custodio de Souza, Federal University of
Pelotas, Department of Morphology, E-mail: [email protected]
Etiology of Osteoarthritis
Osteoarthritis is considered a multifactorial disease, the main cause of work disability
in individuals over 50 years of age. The available epidemiological studies indicate that OA
affects 10-15% of the world population, with an incidence of 60% in men and 70% in women
over 65 years of age. There are likely to increase the incidence of this disease in the coming
decades, becoming an issue of increasingly important public health [1].
The main risk factors for OA are advancing age, genetic predisposition, mechanical stress
and a sedentary lifestyle. However, there are factors that directly interfere in its prevalence,
such as sex, trauma, inflammatory diseases, obesity (which accelerates the degradation
process), primary changes in cartilage, heredity (woman), mechanical, hormonal and
metabolic factors, and infections (Table 1).
System factors
Biomechanical factors
Gender
Body Weight
Age
Injuries and Acquired Deformities
Ethnicity
Overload and Joint Impact
Genetic Factors
Strength Muscular
Endocrine Factors (Hormones)
Metabolic Factors
Nutritional Factors
Table 1: Etiology of Osteoarthritis
It is believed that the etiology of osteoarthritis is related to a lack of adaptation to the
functional demands of the body, i.e., surges, macro traumas or micro traumas [2-7]
The OA can be classified as primary (idiopathic) when its etiology is not well defined and
secondary when there is a specific disease-causing process [2].
The primary is localized or widespread, more common in women, in middle age and
progresses slowly as an accentuation of the normal aging process of the joint (Figure 1).
Affects many joints exist without previously known anomaly, being aggravated by overuse
[8].
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Figure 1: Osteoarthritis in the joint of hand and knee respectively.
The secondary is the result of genetic factors, trauma, more common in men at any
age, inflammatory, neuropathic, metabolic or endocrine diseases result from congenital
abnormality of the joint, joint infection, inflammatory disorders, metabolic arthritis,
hemochromatosis repeated, traumatic injuries and deformities, acquired articular
incongruity, joint misalignment or instability of the joint. Therefore, most of the cases
are secondary to osteoarthritis another condition. The most commonly affected joints are
the knees, hips, hands, neck, and lumbar spine. Other joints, such as shoulders, wrists,
elbows, are rarely affected. Studies have shown that another joint has been greatly affected,
Temporo-mandibular Join (TMJ) [2,4,8,9].
One of the most accepted hypotheses would be a defect in the articular cartilage or
collagen metabolism. Among the genes potentially involved in the disease are: Insulin-like
Growth (IGF-I and IGF-II) factor of the Vitamin D Receptor (VDR), oligomer proteins of
cartilage matrix and regions of the Human Leukocyte Antigen (HLA). There seem loci linked
to osteoarthritis in areas of chromosomes 2q and 11q [10]. Although the hypothesis of
defects in structural proteins such as collagen type II and IX have been proposed, there is
no concrete evidence of their involvement in disease occurrence. Osteoarthritis results from
an imbalance in the metabolic processes mediated by chondrocytes and is characterized by
a gradual degradation of extracellular matrix components of fibrocartilage, with or without
secondary inflammatory factors [3,8,10,11].
Pathophysiology of Osteoarthritis
Osteoarthritis (OA) is a degenerative joint disease, chronic and progressive, affecting
synovial joints mobile [2,12,13]
These processes result in different interactions between the joint cartilage and adjacent
tissues in response to injury or chondrocyte extracellular matrix [14,15]. This disease can
affect upper and lower limbs. From the lesion starts matrix degradation by proteolytic
enzymes such as Matrix Metalloproteinase (MMPs). The specific collagenases include MMP1 (collagenase up-1), MMP-8 (collagenase-2) and MMP-13 (collagenase-3). These enzymes
are distinguished by the ability to degrade other regions of the triple helical helix of type
I collagen, II and III. The gelatinases MMP-2 (gelatinase A) and MMP-9 (gelatinase B) is
another group of enzymes that degrade collagen types IV, V, VII and XI. This group acts
synergistically with collagenase in cleavage of collagen. In addition, degrade elastin, agrecans
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and cartilage link protein. Other enzymes are also able to degrade extracellular matrix, such
as cathepsin D, degrade agrecans; cathepsins B and L cleave telopeptides regions of collagen
types I and II resulting in depolymerized collagen fibrils, agrecans and helical regions of the
collagen IX and XI. There are still serine proteases, such as plasmin, which directly degrade
extracellular matrix, or by activating metalloproteinase precursors [16].
At the same time, the cartilage components are organized to control progression
degeneration [3,15]. The decomposition of proteoglycan and collagen bundles triggers
increased amount of water, the space between the fibrils followed by a superficial necrosis
of chondrocytes and reduced density of these cells. Consequently, the joint surface will
change affecting the joint capsule, subchondral bone, ligaments, muscles and tendons,
including the synovial fluid. Increased hydration of cartilage and proteoglycans, promotes
changes in mechanical properties of the tissue, triggering the loss of integrity of the articular
surface and the presence of vertical cracks progressing to deep erosions with the consequent
exposure of the subchondral bone [2,3,14]. These conditions cause pain, swelling and loss
of joint mobility in osteoarthritis [3,14].
Acute pain of early osteoarthritis usually has a tendency to disappear within one year
after having emerged, but may return and become chronic if no maintenance. Thus,
immediate and proper treatment of osteoarthritic pain is crucial to maintain mobility and
quality of life of the individual [17].
Joint Structures
The joint surfaces are covered by hyaline cartilage (articular cartilage), surrounded by
a fibrous capsule formed by connective tissue integrating bone components maintained by
ligaments. The adult articular cartilage has a limited capacity for regeneration due to the
absence of blood vessels and lower mitogenic potency of chondrocytes. These cells present
in small proportions are considered the metabolic center and producer extracellular matrix
found in cartilage, composed mainly of water, proteoglycans, collagen and other proteins.
The self-regeneration is not possible. Depending on the location and size of a defect in the
cartilage will progress and will eventually lead to osteoarthritis. Therefore, pathogenesis of
osteoarthritis involves a change in the phenotype of the chondrocytes, which is mediated by
different signals, autocrine and paracrine that lead to the synthesis of many inflammatory
mediators and degradation of extracellular matrix [8,14].
The articular surfaces (inner layer of the capsule) formed by synovial cellular layer (synovial
membrane), type B synovial cells, which provide oxygen and nutrients to the chondrocytes
of articular cartilage. Type A cells are macrophages of the joint cavity. Cytokines produced
by the synovia and chondrocytes also play an important role in cartilage degradation,
Especially Interleukin (IL1) and Tumor Necrosis Factor (TNF), and Prostaglandins (PGs) and
leukotrienes. Nitric oxide, whose production is stimulated by proinflammatory cytokines
is involved in cartilage catabolism and can induce apoptosis of chondrocytes. The synovial
fluid of patients with osteoarthritis occurs as a series of changes in the concentrations
of MMP-1 and stromelysin, reduction of the concentration and size of the molecules of
hyaluronic acid and increased levels of cartilage oligomeric matrix proteins [3,14].
Symptoms of osteoarthritis
Osteoarthritis pain has many symptoms, which generally comprise those caused by
mechanical or chemical stimulation [17].
Pain is the first symptom of inflammatory process such as osteoarthritis. This is triggered
by degenerative changes (bone remodeling, subchondral micro fractures, periostitis, and
nerve compression by osteophytes) that occur in conjunction with osteoarthritis (Table 2).
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Osteoarthritis is characterized by the gradual development:
1. Joint Paint
2. Inelasticity
3. Paresthesia sensation of upper and lower limbs
4. Limitation of movement
5. Deformities
Table 2: Clinical Manifestations of Osteoarthritis
These features help in the diagnosis of osteoarthritis compared to other joint conditions,
for example, rheumatoid arthritis. Occasionally synovial acute or sub-acute inflammation
can occur in osteoarthritis, inflammatory pain feature that can be observed [4].
Early in the process, the pains are sporadic with aggravating the injury, intense. May
still be ongoing and waking the patient at night. Others factors that contribute to the pain
process are the periarticular muscle spasm, reduced blood flow, increased intraosseous
pressure and synovial inflammation, release of chemical mediators including cytokines,
prostaglandins, bradykinin, leukotrienes, potassium and hydrogen ions, histamine,
serotonin and substance P, among others. Substances like as bradykinin, hydrogen ions,
serotonin and substance P activates directly the sensation of pain (algesia). Furthermore,
Prostaglandins (PGs), leukotrienes and cytokines seem to increase the sensitivity of the
nociceptors present in periarticular [3]. These symptoms are common to osteoartritis of the
affected joints and the rarest (Table 3).
TABLE 3
Sites of osteoarthritis:
Hands joints (commom)
Knee joints (commom)
Shoulder joints (commom)
Hip joints (commom)
Joints of Ankles (commom)
Foot joints (commom)
Spinal joints (commom)
Elbow joints (rare)
Wrist joints (rare)
Increased Volume Articular
The volume joint can be increased because an amount of synovial fluid or the presence
of osteophytes. A higher sensitivity is observed in articular margins, the capsule insertion
points and periarticular tendons. This increase in joint volume can form bone nodules joint.
Distal interphalangeal joints, Heberden nodes and proximal interphalangeal, Bouchard’s
nodes. Often occurs palmar and lateral deviation of the distal phalanges, due to the presence
of Heberden nodes. These are more prevalent in females and appear to be associated with
family conditions [18].
Joint stiffness
A common complaint is rigidity to rise, but is short-lived. This condition helps in the
diagnosis. The stiffness can remain for more than 1 hour [4,8].
Instability of Movements
Disease progression cause the movement limitation associated with muscle spasm,
contraction of the capsule and osteophytes (mechanical limit) or intra-articular bodies [4,8].
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Pharmacologic Treatment
Treatment should also be multidisciplinary and seek functional improvement, mechanical
and clinical. The main indication for the treatment of osteoarthritis pain is drug therapy.
To moderate osteoarthritis pain can be relieved with the common analgesics. Patients with
more severe painful symptoms that do not respond to non-steroidal analgesic or common
anti-inflammatory drugs in suitable doses or have contraindications to the use thereof,
requiring, sometimes, the opioid analgesics.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) are widely used to reduce pain and
inflammation, as well as improving function in patients with osteoarthritis. The inhibition
of the cyclooxygenase enzyme in the production of prostaglandins is one of mechanisms in
pain control.
The non-steroidal anti-inflammatory drugs are widely used for pain associated
with osteoarthritis, because they act in specific inhibition of Cyclooxygenase (COX) and
consequently in reduction of peripheral and central prostaglandins.
The administration of an NSAID, did not completely relieve the pain associated with
osteoarthritis and also does not alter the course of the pathological condition (Table 1).
There are other factors involved in the progress of degenerative change in the production
of inflammatory mediators and pain associated with the disease. In all cases of osteoarthritis
is necessary to recognize that treatment may not only involve the use of medications. You
need to minimize physical stress on the joints. However, a targeted physical activity and
interleaved with rest, beware of overweight and avoid repeated movements is indicated
[3,16,19].
Intra-Articular Therapy
The intra-articular therapy is associated with controlling pain and improving joint
function. The intra-articular infiltration with corticosteroids may have control of pain and
inflammation. It has also been used intra-articular hyaluronic acid is indicated for the
treatment of osteoarthritis of the knee grade II and III in the acute and chronic phases.
In addition to corticosteroids chondroprotective the Connective Tissue Structure-Modifying
agents is used (CTSMAs) and Disease-Modifying OA Drug (DMOAD) [20].
Non-pharmacological Therapies
In cases of osteoarthritis recommended the strengthening of muscle mass-Aerobic
physical conditioning and stretching.
Orthotics and equipment aid the march can also be displayed when there is need
to improve, assist or replace a function. Medial stabilization of the patella is effective in
treating painful symptoms of osteoarthritis. To stabilization ankle an insoles are effective in
improving pain and function in osteoarthritis of the medial compartment of the knee.
Thermotherapy, analgesic electrotherapy and Transcutaneous Electrical Nerve Stimulation
(TENS) are effective means supporting the symptomatic treatment of pain [21-25].
Surgical Treatment
With progressive impairment of osteoarthritis and some daily activities is indicated
surgery. The surgeries are indicated: arthroscopic debridement, osteotomies and
arthroplasties [24,25].
Stem Cells
The implant autologous (one’s own) stem cells (cartilage and adipose tissue) is being
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extensively studied worldwide. This treatment consists of collecting cartilage cells and
growing them, and then reapply the site of injury [26,27].
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