Pathophysiology of

Musculoskeletal System
Disorders
Overview
Asst. Prof. Ali Timucin Atayoglu
 Key facts
• Approximately 1.71 billion people have musculoskeletal conditions worldwide.
• Among musculoskeletal disorders, low back pain causes the highest burden with a prevalence
of 568 million people.
• Musculoskeletal conditions are the leading contributor to disability worldwide, with low back
pain being the single leading cause of disability in 160 countries.
• Musculoskeletal conditions significantly limit mobility and dexterity, leading to early
retirement from work, lower levels of well-being and reduced ability to participate in society
• Because of population increases and ageing, the number of people with musculoskeletal
conditions is rapidly increasing.
• The disability associated with musculoskeletal conditions has been increasing and is projected
to continue to increase in the next decades.
 Scope
• Musculoskeletal conditions comprise more than 150 conditions that affect the locomotor system of
individuals. They range from those that arise suddenly and are short-lived, such as fractures, sprains
and strains, to lifelong conditions associated with ongoing functioning limitations and disability.
• Musculoskeletal conditions include conditions that affect:
• joints, such as osteoarthritis, rheumatoid arthritis, psoriatic arthritis, gout, ankylosing
spondylitis;
• bones, such as osteoporosis, osteopenia and associated fragility fractures, traumatic
fractures;
• muscles, such as sarcopenia;
• the spine, such as back and neck pain;
• multiple body areas or systems, such as regional and widespread pain disorders and
inflammatory diseases such as connective tissue diseases and vasculitis that have
musculoskeletal manifestations, for example systemic lupus erythematosus.
 Pathophysiology of Inflammation
• The initial inflammation phase consists of three subphases: acute, subacute,
and chronic (or proliferative).
• The acute phase typically lasts 1–3 days and is characterized by the five
classic clinical signs: heat, redness, swelling, pain, and loss of function.
• The subacute phase may last from 3–4 days to ~1 mo and corresponds to a
cleaning phase required before the repair phase.
• If the subacute phase is not resolved within ~1 mo, then inflammation is said to become
chronic and can last for several months. Tissue can degenerate and, in the locomotor
system, chronic inflammation may lead to tearing and rupture.
• Alternatively, after the subacute inflammatory phase, tissue can repair and be
strengthened during the remodeling phase.
• From a mechanistic point of view, the acute response to tissue injury
occurs in the microcirculation at the site of injury.
• Initially, there is a transient constriction of arterioles; however, within
several minutes, chemical mediators released at the site relax arteriolar
smooth muscle, leading to vasodilation and increased capillary
permeability.
• Protein-rich fluid then exudes from capillaries into the interstitial space.
This fluid contains many of the components of plasma including albumin,
fibrinogen, kinins, complement, and immunoglobulins that mediate the
inflammatory response.
Chemical Mediators of Inflammation
• Biochemical mediators released during inflammation intensify and propagate the
inflammatory response . These mediators are soluble, diffusible molecules that can act
locally and systemically. Mediators derived from plasma include complement and
complement-derived peptides and kinins.
• Released via the classic or alternative pathways of the complement cascade,
complement-derived peptides (C3a, C3b, and C5a) increase vascular permeability, cause
smooth muscle contraction, activate leukocytes, and induce mast-cell degranulation.
C5a is a potent chemotactic factor for neutrophils and mononuclear phagocytes.
• The kinins are also important inflammatory mediators. The most important kinin is
bradykinin, which increases vascular permeability and vasodilation and, importantly,
activates phospholipase A2 (PLA2) to liberate arachidonic acid (AA).
• Bradykinin is also a major mediator involved in the pain response.
• Cytokines, including interleukins 1–10, tumor necrosis factor α (TNF-α), and
interferon γ (INF-γ) are produced predominantly by macrophages and lymphocytes but
can be synthesized by other cell types as well. Their role in inflammation is complex.
These polypeptides modulate the activity and function of other cells to coordinate and
control the inflammatory response.
• By increasing intracellular Ca2+ concentrations in leukocytes, cytokines are also important
in the induction of PLA2.
• Colony-stimulating factors (GM-CSF, G-CSF, and M-CSF) are cytokines that promote
expansion of neutrophil, eosinophil, and macrophage colonies in bone marrow.
• In chronic inflammation, cytokines IL-1, IL-6, and TNF-α contribute to the activation of
fibroblasts and osteoblasts and to the release of enzymes such as collagenase and
stromelysin that can cause cartilage and bone resorption. Experimental evidence also
suggests that cytokines stimulate synovial cells and chondrocytes to release pain-inducing
mediators.
Pathophysiology of musculoskeletal pain
• Musculoskeletal pain affects more than 30% of the global population and
imposes an enormous burden on patients, families, and caregivers related
to functional limitation, emotional distress, effects on mood, loss of
independence, and reduced quality of life. The interplay of neurons and
non-neural cells (e.g. glial, mesenchymal, and immune cells) amplifies
and sensitizes pain signals in a manner that leads to cortical remodeling.
• Chronic musculoskeletal pain is defined as a pain perceived in
musculoskeletal tissues that lasts or recurs for more than 3 months, and is
characterized by significant functional disability and emotional distress. Pain
is categorized as primary chronic pain if it cannot be directly attributed to a
known disease or damage process, or as secondary if it is caused by a disease
or process that directly affects the bones, joints, muscles, and/or related soft
tissues. It follows that chronic musculoskeletal pain has a major social and
emotional impact that can include decreased socialization, inability to work,
loss of independence, anxiety, depression, and concern for the future.
BONE DISEASES
• Bone remodeling : Osteoclasts, derived from hematopoietic precursors, are responsible for bone resorption.
Osteoblasts, from mesenchymal cells, are responsible for bone formation.
• The balance of bone formation and bone resorption tends to be negative with age, particularly in post-menopausal women,
often leading to a loss of bone serious enough to cause fractures, which is called Osteoporosis.
• Osteoporosis. In Osteoporosis the mineral-to-collagen ratio is within the reference range. In menapouse, estrogen deficiency
may lead to increased expression of RANKL by osteoblasts and decreased release of OPG; increased RANKL results in
recruitment of higher numbers of preosteoclasts as well as increased activity, vigor, and lifespan of mature osteoclasts.
• Ostomalacia is caused by Vitamin D deficiency or phosphate deficiency. In Osteomalacia, the proportion of mineral
composition is reduced relative to organic material content
• Osteopetrosis is a sclerosing disease which is more or less the opposite of osteoporosis, results from a variety of genetic
defects that impair the ability of osteoclasts to resorb bone and leads to excessive bone accumulation. Osteopetrosis is
characterized by the failure of osteoclasts to resorb bone and occurs in association with renal tubular acidosis and cerebral
calcification due to carbonic anhydrase isoenzyme II deficiency .
• Paget disease is characterized by an increase in bone loss due to excess numbers of overactive osteoclasts, while bone
formation increases to compensate for the loss, and the rapid production of new bone leads to a disorganized bone structure.
• Osteogenesis Imperfecta is a developmental disease with pathologic changes seen in all tissues of which type 1 collagen is
an important constituent (eg, bone, ligament, dentin, and sclera) and the basic defect is one of a qualitative or quantitative
reduction in type 1 collagen.
JOINT DISEASES
• Osteoarthritis, also known as degenerative joint disease, is a disease of synovial joints.
• Osteoarthritis is characterized by progressive deterioration and loss of articular cartilage with concomitant
structural and functional changes in the entire joint. Normally, cartilage undergoes a stimulated by joint movement
or use.
• In Osteoarthritis, remodeling process is altered by a combination of mechanical, cellular, and biochemical
processes, resulting in abnormal reparation of cartilage and an increase in cartilage degradation. The inflammation
that occurs typically involves the periarticular tissues and is generally milder in severity compared to Romatoid
Arthritis.
• In Osteoarthritis cartilage, however, matrix degrading enzymes are overexpressed, shifting this balance in favor of
net degradation, with resultant loss of collagen type II and proteoglycans from the matrix. The primary enzymes
responsible for the degradation of cartilage are categorized into three general categories: a) collagenases; b)
stromelysins; and, c) gelatinases.
• Romatoid Arthritis is an autoimmune disease.
• The initial triggers of Romatoid Arthritis can be hormones, genetics and environmental factors may all play a
role. Once the initial immune response is triggered, cells of the immune system produce autoantibodies and
inflammatory cytokines, creating a cascade of inflammation resulting in the formation of pannus; the pannus
invades and destroys cartilage and bone.
• Rheumatoid arthritis is characterized by the presence of autoantibodies known as rheumatoid factors (RF) and
anti-citrullinated peptide antibodies (ACPA, which includes the anti-cyclic citrullinated peptide antibody or anti-
CCP).
MUSCULAR DISEASES
• Polymyositis is a rare type of inflammatory myopathy, a group of muscle diseases that cause
inflammation of muscle and their associated tissues, including blood vessels,
• Polymyositis may be caused by the direct cytotoxic effect of CD8+ lymphocytes on muscle.
• Dermatomyositis is an idiopathic inflammatory myopathy with characteristic cutaneous(skin)
findings.
• Dermatomyositis may be caused by complement-mediated (terminal attack complex) vascular
inflammation.
• Musculor Dystrophies are related to sarcolemmal stability, dystrophin and the dystrophin-associated
glycoproteins are important elements. They can be Sex-linked (- Duchenne, Becker, Emery-Dreifuss),
Autosomal dominant ( - Facioscapulohumeral, distal, ocular, oculopharyngeal) or Autosomal recessive
(Limb-girdle form)
• Myasthenia gravis is the most common chronic autoimmune neuromuscular disorder of skeletal
muscle nicotinic acetylcholine receptor (nAChR) that causes weakness of the skeletal muscles,
resulting from impaired communication between nerve cells and muscles.
• Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that in general implicated defects in
the proteasome system were considered as a possible mechanism