Pathophysiology of
musculoskeletal system
Bone properties
• Bones
• stiff
• do not bend when loaded.
• flexible - absorb the energy imposed by
loading as potential energy by elastic
then plastic deformation.
• Structural failure may occur if bones
deform too little or too much.
• High remodeling reduces the mineral
content of bone, resulting in loss of
stiffness.
Bone remodelling
Bone remodeling
• Osteoclast activation
• Resorbtion phase- due to osteoclast activation- short period
• Reverse phase- bone surface is covered by mononuclear cell
• Formation phase- osteoblast production in bone matrix - long.
Bone remodeling
• tightly coordinated
• requires the synchronized action of osteoclasts, osteoblasts, bone-lining cells and osteocytes
• in a microanatomical structure separated from the bone marrow cavity by a canopy of cells but
accessible through microcapillaries
• process starts with the retraction of bone-lining cells covering the bone surface and the
recruitment of osteoclast precursors to this remodeling site.
Mature osteoclasts
• large, multinucleated, short-lived, highly
active cells attached to the bone surface
• responsible for the dissolution of the
minerals and enzymatic degradation of
the remaining organic matrix.
• after osteoclast-mediated resorption is
complete, collagen remnants are removed
• resorption lacunae is prepared for
subsequent osteoblast-mediated bone
formation in a process that is still poorly
understood. orthobullets.com/basic-science/9002/bone-cells
Bone formation
• starts with the differentiation of
osteoblasts and laying down of the
organic osteoid, consisting mainly of
collagen type I.
• completed after osteoblast-mediated
mineralization of the organic matrix.
• resting bone surface covered by bonelining
cells belonging to the osteoblast
lineage is re-established
The osteoblast lineage derives from MSCs under the control of the transcriptional regulator
RUNX2. The multipotent differential capacity of MSCs can also give rise to chondrocyte,
adipocyte, myocyte and other cell lineages, utilizing lineage-specific transcription factors SOX9,
PPARγ2 and MYOD/MYF5, respectively. RUNX2 is indispensible in all stages of osteoblast
differentiation. After reaching maturity, three different potential fates await osteoblasts. Cells
that become entombed within the bone matrix are called osteocytes, bone-lining cells cover all
bone surfaces while the remainder undergo apoptosis
Osteocytes
• terminally differentiated
osteoblasts entombed within the
bone matrix
• account for almost 95% of all cells
in the mature bone tissue – form a
network of canaliculi within the
mineralized bone.
• mechanosensing cells - detect
mechanical strain and associated
bone microdamage
• respond by initiating bone
resorption and the regulation of
bone remodeling.
Bone, Volume 42, Issue 4
RANK/RANKL/OPG system
• one of the most important regulators of bone
resorption and remodeling
• RANK, located on the surface of osteoclasts and
their precursors, and its ligand RANKL are
essential for the formation, differentiation,
activity and survival of osteoclasts.
• RANKL is produced by cells of the osteoblast
lineage as well as other cell types in both soluble
and membrane-bound forms.
• The binding of RANKL to RANK, results in the
activation of transcription factors NFκB and
NFATC1 and the expression of osteoclastogenic
genes.
• OPG, secreted by osteoblasts and a few other
cell types, functions as a decoy receptor by
binding to RANKL, thereby preventing the
activation of RANK.
• inhibition of RANKL leads to the rapid arrest of
osteoclast formation, activation and survival, is
crucial for the suppression of bone resorption
and maintenance of bone mass
RANK/RANKL/OPG system.The RANK/RANKL/OPG system is essential for the formation and differentiation of
osteoclasts, their resorptive activity and survival. The binding of RANKL to RANK results in the recruitment of TRAF6,
which activates various protein kinase pathways and transcription factors like NFκB. The activated NFκB up-regulates
the expression of C-FOS, which subsequently interacts with NFATC1 to induce the expression of osteoclastogenic
genes. Conversely, OPG prevents the activation of RANK by binding RANKL .
Modulators of RANK/RANKL/OPG system
• Pro-inflammatory cytokines secreted by
different immune cells
• including activated T cells, B cells,
macrophages, mast cells and natural killer
cells
• TNFα, IL1, IL6, IL8, IL11 and IL17
• osteoclastogenic cytokines promoting
RANKL-mediated osteoclast differentiation
and activity,
• IFNγ, IL4, IL10, IL13 and IL18
• anti-osteoclastogenic cytokines IFNβ,
inhibit osteoclasts through the
RANK/RANKL/OPG system.
• Certain cytokines can exert opposite
effects on osteoclasts (e.g., IL7 and IL23)
Cytokines and prostaglandins
Osteo-immunomodulatory complex
Osteoclasts activation
• Under pathologic conditions,
inflammatory and malignant
cells can increase osteoclastogenesis
by producing
soluble or membrane-bound MCSF
and RANKL as well as
PTH-related protein (PTHrP),
cytokines, and prostaglandins.
Parathyroid Hormone Relation Peptide (PTHrP)
• PTHrP was discoverde as mediator of syndrome "humoral hypercalcemia
of malignancy" (HHM).
• During the syndrome inn different type of cancer (in absebce of metastases)
similar compounds to PTH are produceds which is related to:
• Hypercalcemia
• Hypophosphatemia
• Increased cAMP exctretion by urine
• The effects are similar to those caused by PTH; no PTH levels are detected.
Gene Mutation Disease
RANK
18 bp duplication Familial expansile osteolysis
27 bp duplication Early onset Paget’s disease
15 bp duplication
Expansile skeletal
hyperphosphatasia
RANKL
Deletion of amino acids 145-177
Autosomal recessive
osteopetrosis
A single nucleotide change (596T-A) in exon 8 of
both alleles
Autosomal recessive
osteopetrosis
Deletion of two nucleotides (828_829delCG)
Autosomal recessive
osteopetrosis
OPG Deletion making OPG inactive Juvenile Paget’s disease
20 bp deletion resulting in premature termination
of OPG translation
Juvenile Paget’s disease
Collagen abnormalities
• A polymorphism of the first intron of the gene coding for the type I
collagen 1 chain and increased levels of homocysteine can influence
fracture risk independent of BMD (bone mass density).
• This may be due to differences in helix formation or cross-linking of collagen,
challenging the concept that mineral and matrix composition are normal in
osteoporosis and that only structural abnormalities account for skeletal
fragility.
Bone - pathophysiology
Skeletal fragility
Skeletal fragility can result from:
• failure to produce a skeleton of optimal mass and
strength during growth;
• excessive bone resorption resulting in decreased
bone mass and microarchitectural deterioration of
the skeleton;
• and an inadequate formation response to
increased resorption during bone remodeling.
Bone remodelling defects
• Osteoporosis
• Osteodystrophy
• Rachitis/osteomalacia
• Paget`s disease
Metabolic bone diseases
• Osteoporosis remains the most common metabolic abnormality of bone. It has
been described as “a silent epidemic” affecting one in two women and one in
five men, older than 50 years of age, during their lifetime.
• It is now defined as a systemic skeletal disease characterized by low bone
mass and micro-architectural deterioration of bone resulting in fractures with
little or no trauma.
Osteoporosis
• The bone mass of an individual in later life is a result of the peak bone mass
accrued during intrauterine life, childhood, and puberty, as well as the
subsequent rate of bone loss.
• Although genetic factors strongly contribute to peak bone mass,
environmental factors in intrauterine life, childhood, and adolescence
modulate the genetically determined pattern of skeletal growth.
Osteoporosis
• is a skeletal disease characterised by low bone mass and
microarchitectural deterioration with a resulting increase in bone fragility
and hence susceptibility to fracture.
• Caucasin population: about 50% of women and 20% of men older than
50 years will have a fragility fracture in their remaining lifetime.
Etiopathogenesis of osteoporosis
• complex interactions among local and systemic regulators of bone cell function.
• The heterogeneity of osteoporosis may be due to
• differences in the production of systemic and local regulators,
• changes in receptors,
• signal transduction mechanisms,
• nuclear transcription factors, and
• enzymes that produce or inactivate local regulators.
• Since the first human osteoporosis study indicated an association among bone mass, fragility,
and polymorphisms in the vitamin D receptor (VDR) gene, more than 30 candidate genes have
been reported that might influence skeletal mass and fragility.
• Since osteoporosis is a complex, polygenic disorder, the contributions of specific gene
polymorphisms are likely to be relatively small, but may still be clinically important.
Osteoporosis - causes
• Glucocorticoids excess
• Estrogene deficiency
• Vitamin K2 deficiency
• Immobilization
Estrogen influence on bone state
• Estrogen is critical for
• epiphyseal closure in puberty in both sexes and
• regulates bone turnover in men as well as women.
• Estrogen has a greater effect than androgen in inhibiting bone
resorption in men, although androgen may still play a role.
• Estrogen may also be important in the acquisition of peak bone
mass in men.
• Osteoporosis in older men is more closely associated with low
estrogen than with low androgen levels.
Central role of estrogen deficiency - today
• An increase in bone resorption, and not impaired bone formation,
appears to be the driving force for bone loss in the setting of
estrogen deficiency.
• The rapid and continuous bone loss that occurs for several years
after the menopause indicate an impaired bone formation response,
since in younger individuals going through the pubertal growth spurt,
even faster rates of bone resorption can be associated with an
increase in bone mass.
• However, the increased bone formation that normally occurs in
response to mechanical loading is diminished in estrogen deficiency,
suggesting estrogen is both anti-catabolic and anabolic.
Copyright ©2005 American Society for Clinical Investigation
Raisz, L. G. J. Clin. Invest. 2005;115:3318-3325
Remodelling of bones. Estrogen action
places (i)
Osteoporosis induced by cortisol
• Cortisol modifies proliferative
and metabolic activities of bone
cells
• Cortisol inhibits
osteoblastogenesis
• Reduces half-life time of
osteoblasts which is leading to
decreased bone formation
Common adverse effects of glucocorticoid therapyglucocorticoid-induced
osteoporosis
• Glucocorticoid-induced osteoporosis is the most common type of iatrogenic
osteoporosis and a frequent cause of secondary osteoporosis.
• An estimated 50% of patients taking glucocorticoids for longer than 6 months will
develop secondary osteoporosis.
• The absolute risk for glucocorticoid-induced osteoporosis is higher in patients aged 65
years or older given their baseline age-related fracture risk, although the relative risk
of fracture related to glucocorticoid use may be even higher in patients under 65.
o cofactor for γ-carboxylase, enzyme which catalyses conversion of specific residuals of glutamic acid to
Gla residuals
o γ-carboxylation of proteins of bone matrix which contain Gla as MGP (= matrix Gla protein) a osteokalcin.
o Uncompleted γ-carboxylation of osteocalcin and MGP during vitamin K decrease lead to osteoporosis
and high risk of fractures.
o stimulates synthesis of osteoblastic markers and bone deposition.
o decreases bone reabsorbtion by inhibition of osteclasts formation and by decrease of their resorbtion
activity.
o Vitamin K2 treatment induces osteoclast apoptosis, but inhibits osteoblasts apoptosis which is leading to
increased bone formation.
o Vitamin K2 supports osteocalcin expression ( increases its mRNA) which can be further modulated by 1,
25-(OH)2 vitamin D3.
Vitamin K and bones
Vitamin K2 is
transcription regulator od
specific bone genes,
functioning using SXR
which will lead to
increase of osteoblastic
markers expression.
SXR originally identifies
as xenobiotic sensor…
Cortisol generally
antagonizes
insulin …
Expected reciprocal regulation of endocrine function of adipose tissue and bone:
Carboxylated osteocalcin (OCN) is produced by osteoblasts and is subsequently bound to the hydroxyapatite mineral of mature bone.
During bone resorption controlled by osteoclasts, it is released into the circulation uncarboxylated osteocalcin ucOCN from which it significantly promotes
pancreatic insulin production. Insulin increases the expression of OCN by osteoblasts and at the same time promotes its decarboxylation by osteoclasts. Insulin
also has a positive effect on leptin secretion by adipocytes, leading to inhibition of bone production and resorption by the hypothalamic effect of leptin. The
production of ucOCN is thus reduced and the orexigenic effects of ucOCN on insulin production by the pancreas are modulated.
Osteodystrophy
• Primary
hyperparathireoidism
• Symptoms: chronic
hypecalcaemia,
nephrocalcinosis,
osteodystrophy as a
manifestation of excessive
bone remodeling.
Osteodystrophy
• Secondary hyperparathyroidism usually
in chronic kidney disease with a
tendency to develop chronic renal
failure due to the inability of the
kidneys to resorb calcium-renal
osteodystrophy as a manifestation of
excessive bone remodeling.
• Other causes-usually nutritional:
calcium and phosphate deficiency in
the diet, excess phosphate in the diet.
Wheeless` Textbook of Orthopaedics
Renal Spondyloarthropathy
- seen in hemodialysis patients with chronic renal failure
- typically invovles three adjacent vertebrae with intervening discs;
- changes include
- subluxation, degeneration, and narrowing of disc;
- although the process may resemble infection, it probably represents crystal or
amyloid deposition;
- bone disease is a major complication of uremia and persists and sometimes
worses even after the initiation of hemodialysis;
- when bone disease becomes severe, spontaneous fractures may occur, esp in the
ribs, pelvis, and hips;
- uremic pts with advanced hyperparathyroidism appear prone to non-traumatic
aseptic necrosis of the hips;
- 20% of pts with renal osteodystrophy also show osteosclerosis, most frequently in
the spine, but may also occur in long bones;
- osteomalacia is commonly seen in patients on hemodyalysis therapy for chronic
renal failure;
Osteomalacia and rickets
• Classically, the deficiency of vitamin D, essential for the
absorption of calcium, has been the major cause of rickets in the
child and osteomalacia in the adult
• resulting in absence or delay in the mineralization of growth
cartilage or newly formed bone collagen.
Osteomalacia and rickets
• A consequence of a low serum phosphate and normal serum
calcium.
• Two such conditions are x-linked hypophosphatemic
rickets/osteomalacia and oncogenic osteomalacia.
• When present, the signs of rickets and osteomalacia in the low
serum phosphate states are indistinguishable from the classic
hypocalcemic states.
X-linked hypophosphatemic osteomalacia
• The condition is characterized by
low tubular reabsorption of
phosphate in the absence of
secondary hyperparathyroidism.
• X-linked hypophosphatemia
occurs in about 1 in 25,000 and is
considered the most common
form of genetically induced
rickets.
Oncogenic osteomalacia
• Oncogenic osteomalacia is a paraneoplastic syndrome in which a
bone or soft tissue tumor or tumor-like lesion induces
hypophosphatemia and low vitamin D levels that reverse when
the inciting lesion is resected.
Oncogenic osteomalacia
• Phosphotonin
• a humoral factor,
• has been identified in clinical and experimental studies as being responsible for the serum
biochemical changes.
• causes hyperphosphaturia by inhibiting the reabsorption of phosphate by the proximal renal
tubules.
• Fibroblast growth factor 23, phosphate-regulating gene with homologies to endopeptides
located on the ‘x’ chromosome (PHEX) and matrix extracellular phosphoglycoprotein
(MEPE) are candidates proposed for the production of phosphatonin and the altered
pathophysiology in oncogenic osteomalacia.
Paget's Disease
• abnormal bone remodeling
• active interplay between excessive bone resorption and
abnormal new bone formation
• Pathophysiology causes
• genetic predisposition
• slow virus infection (intra-nuclear nucleocapsid-like structure)
•paramyxovirus
•respiratory syncytial virus
•Epidemiology
• peak incidence in the 5th decade of life
• common in Caucasians
• males = females
• location
• monostotic or polyostotic
• common sites include femur > pelvis > tibia > skull > spine
• Signs and symptoms
• Majority asymptomatic
• Skull: deformity with emlargement, hearing loss, dizziness
• Spine and pelvis: bone pain, spinal stenosis, nerve compression
• Long bones: defformities with increased fracture risk
Laboratory findings
•elevated serum ALP
•elevated urinary collagen cross-links
•elevated urinary hydroxyproline
(collagen breakdown marker)
•increased urinary N-telopeptide,
alpha-C-telopeptide,
and deoxypyridinoline
•normal calcium levels
Paget's Disease - genetics
Genetics
•inheritance
•most cases are spontaneous
•hereditary
•familial clusters have been described with ~40% autosomal dominant transmission
•genetics
•most important is 5q35 QTER (ubiquitine binding protein sequestosome 1) SQSTM1 (p62/Sequestosome)
•tend to have severe Paget disease
•also insertion mutation in TNFRSF11A for gene encoding RANK
Nature Reviews Rheumatology volume 5, pages483–489(2009) Nature Clinical Practice Rheumatology volume 2, pages270–277(2006)
IBM = inclusion body myopathy
FEO = Familial expansile osteolysis
Joints
Articular diseases
• irreversible destruction of the cartilage,
tendon, and bone that comprise synovial
joints
• rheumatoid arthritis (RA) and
• osteoarthritis (OA).
• While cartilage is made up of
proteoglycans and type II collagen,
tendon and bone are composed primarily
of type I collagen.
Rheumatoid Arthritis
• The prevalence of rheumatoid arthritis in most Caucasian populations approaches
1% among adults 18 and over and increases with age, approaching 2% and 5% in
men and women, respectively, by age 65
• The incidence also increases with age, peaking between the 4th and 6th decades
• Both prevalence and incidence are 2-3 times greater in women than in men
• Monozygotic twins 13.5% vs dizygotic twins 3.5%
“One must from time to time attempt things that are
beyond one’s capacity.”
—Pierre-Auguste Renoir
Rheumatoid Arthritis
• Rheumatoid arthritis is an autoimmune
disease affecting the joints, tendons, and
bones, resulting in inflammation and
destruction of these tissues.
• The term ‘arthritis’ is used to denote
clinically apparent soft tissue swelling or
fluid (not bony overgrowth alone).
Rheumatoid arthritis
• characterised by a symmetric
polyarthritis usually involving the
small joints of the hands and feet.
• Extra-articular involvement of organs
such as the skin, heart, lungs, and
eyes can be significant.
Rheumatoid Arthritis
• Description
• Morning stiffness
• Arthritis of 3 or more joints
• Arthritis of hand joints
• Symmetric arthritis
• Rheumatoid nodules
• Serum rheumatoid factor
• Radiographic changes
• having rheumatoid arthritis – positive 4 of 7
criteria, with criteria 1-4 present for at least 6
weeks
Functional Presentation and Disability of RA
• In the initial stages of each joint involvement, there is warmth, pain,
and redness, with corresponding decrease of range of motion of the
affected joint
• Progression of the disease results in reducible and later fixed
deformities
• Muscle weakness and atrophy develop early in the course of the
disease in many people
Clinical Presentation of RA
Early RA Intermediate RA
Severe RA
Latinis KM, et al. The Washington ManualTM Rheumatology
Subspecialty Consult. Philadelphia, Pa: Lippincott Williams
& Wilkins; 2004.
Rheumatoid Arthritis
• Pathogenesis of RA is attributed to a complex interaction between genetic and
environmental factors and the repeated activation of innate and adaptative
immunite system evolves into the breakdown of immune tolerance, aberrant
autoantigen presentation and antigen-specific T and B cells activation.
• Genetic factors have an important role in the susceptibility to rheumatoid arthritis
• HLA-DRB
First step – joint disease?
• Although the synovium is the principal site of pathology in the established phase of disease, it may
not be the site where the disease is initiated.
• Systemic immune abnormalities in individuals without joint symptoms, and a lack of immune
infiltrates in the synovium during the earliest phase before clinical signs and symptoms of arthritis,
point to other tissues being important in the initiation of adaptive immune reactions.
• Important tissues for research include bone marrow, lymph nodes, the gut, periodontal tissue, the
lung and the neuroendocrine system.
McInnes and Schett, NEJM 2011
RA without clinical arthritis
• An initial phase, characterised by systemic autoimmunity without synovial inflammation, may be
followed by a shorter phase during which asymptomatic synovitis is present.
RA without clinical arthritis
• synovial and bone abnormalities (eg, ultrasound or MRI) - changes such
as synovial thickening, increased synovial vascularity and bone marrow
oedema in patients with symptoms without clinical arthritis
RA progression
• events culminate in synovial inflammation, hyperplasia and bone destruction leading to joint
swelling and deformity and to systemic inflammation.
RA progression
• Early Pannus
• Granulation,
inflammation at
synovial membrane,
invades joint, softens
and destroys cartilage
Mod advanced Pannus
joint cartilage disappears,
underlying bone destroyed, joint
surfaces collapse
Fibrous Ankylosis
Fibrous connective tissue replaces
pannus; loss of joint otion
Bony Ankylosis
Eventual tissue and joint
calcification
RA progression
Subcutaneous nodules
(disappear and appear
without warning)
Diagnostic Tools
in Rheumatoid Arthritis
• Rheumatoid factor
• Anti-CCP antibodies
• Plain X-ray
• MRI
• Ultrasound
Rheumatoid Factor
• Antibody directed against the Fc portion of IgG
• Present in approximately 80% of RA patients
• Sensitivity for RA is ~80%
• Specificity is 85-95%
• May be involved in disease pathogenesis
• Higher levels tend to be associated with poorer prognosis
• Found in other conditions, especially Hepatitis C
Anti-Cyclic Citrullinated Peptide (CCP) Antibodies
in RA
• Anti-citrulline Abs produced in RA synovium
• Early RA Diagnosis
• sensitivity 48%; specificity 96%
• seen in 2% of pts with other autoimmune diseases and infections (vs. 14% for
RF)
• less than 1% of healthy controls
• Predicts erosive disease PPV - 63% and NPV - 90%
• Present years before the onset of symptoms. 34% of blood samples
obtained 2.5 yr before onset of symptoms (vs. 1.8% of controls)
Anti-Cyclic Citrullinated Peptide (CCP)
Antibodies in RA
Plain X-ray
Magnetic Resonance Imaging as a Diagnostic Tool
McQueen FM et al. Ann Rheum Dis. 1999;58:156-163.
McQueen FM et al. Ann Rheum Dis. 1998;57:350-356.
14
45
0
10
20
30
40
50
X-ray MRI
Erosions Detected:
X-rays vs MRI (%)
Ultrasound as a Diagnostic Tool
Keen et al. Rheum Dis Clinic N
Am 31 (2005) 699-714
Features Related to Poor Outcomes
 Extra-articular disease
 High rheumatoid factor titer, positive anti-CCP antibody
 Poor functional status
 Involvement of multiple joints
 Radiographic erosions
 Sustained elevation of acute-phase reactants (eg, ESR)
 Low socioeconomic status/educational level
 Increased genetic risk of developing RA plus smoking
Anaya JM, et al. Ann Rheum Dis. 1994;53:782-783. Pincus T, et al. Balliere’s Clin Rheumatol.
1992;6:161-191. Furst DE. Rheum Dis Clin North Am. 1994;20:309-319. Padyukov L, et al. Arthritis
Rheum. 2004;50:3085-3092.
Complications of Rheumatoid Arthritis
• Complications include:
• Carpal tunnel syndrome, Baker’s cyst,
vasculitis, subcutaneous nodules,
Sjögren’s syndrome, peripheral
neuropathy, cardiac and pulmonary
involvement, Felty’s syndrome, and
anemia
Rheumatoid arthritis: episcleritis
Copyright © 1972-2004 American College of Rheumatology Slide
Collection. All rights reserved.
Treatment before the BIOLOGICS
• NSAIDs for stiffness
• Corticosteroids for inflammation and to suppress the
autoimmunity
• Disease Modifying Anti rheumatic Drugs (DMARDs)
• Drug of choice -Methotrexate 7.5-25mg weekly
• But also Cyclosporine, Azathioprine, cyclophosphamide
Pamela E. Prete MD
Monoclonal antibodies and RA
Tumor Necrosis (alpha) Inhibitors 5 FDA approved
 Infliximab ( Remicaid ) an infusion
 Etanercept ( Enbrel) against soluble TNF receptors
 Adalimunab (Humira) against soluble and membrane bound TNF receptors
 Certolizumab (Cimza) pegylated
 Golimumab (Simponi)
Rituximab (rituxan) anti CD20 B cells
Abatacept anti Costimulation blocking CD80/86 CD28
Anakinra (Kineret) anti IL 1 receptor LOW EFFECT
Tocilizumab (Actemra) anti IL 6
RA Therapies: The Next Generation
• Biosimilars
• Anti-IL-6 receptor
• Sarilumab
• Anti-IL-17A
• Secukinumab
• Anti-IL-20
• Anti-CD22
• Epratuzamab
• Chemokine inhibitor: CCX354-L2
• PDE4 inhibitor: aprimilast
Lupus joints
• Almost everyone with SLE has joint pain or inflammation.
• Any joint can be affected, but the most common spots are the
hands, wrists, and knees.
• Usually the same joints on both sides of the body are affected
• The soft tissues around the joints are often swollen, but there
is usually no excess fluid in the joint.
• Many SLE patients describe muscle pain and weakness, and the
muscle tissue can swell.
Seronegative Spondyloarthropathy
• Consist of a group of related disorders that include Reiter's syndrome,
ankylosing spondylitis, psoriatic arthritis, and arthritis in association
with inflammatory bowel disease
• Occurs commonly among young men, with a mean incidence between
ages 25 and 34
• The prevalence is about 1%
• The male-to-female ratio approaches 4 to 1 among adult Caucasians
• Genetic factors play an important role in the susceptibility to each
disease
Seronegative Spondyloarthropathy
• The spondyloarthropathies share certain common features, including the absence of serum
rheumatoid factor, an oligoarthritis commonly involving large joints in the lower extremities,
frequent involvement of the axial skeleton, familial clustering, and linkage to HLA-B27
• These disorders are characterized by inflammation at sites of attachment of ligament, tendon,
fascia, or joint capsule to bone (enthesopathy)
Sacroiliitis
• Sacroiliitis is an inflammation of the
sacroiliac joint.
• Symptoms usually include a fever and
reduced range of motion.
• Picture of individual with – sacroiliitis and
Ankylosing Spondylitis. The arrows point
to the inflamed and narrowed SI joints.
They are white due to bony sclerosis
around the joints
Ankylosing Spondylitis
• Chronic disease that primarily affects the spine
and may lead to stiffness of the back.
• The joints and ligaments become inflamed.
The joints and bones may fuse.
• The effects are inflammation and chronic pain
and stiffness in the lower back that usually
starts where the lower spine is joined to the
pelvis or hip.
• Diagnosis: X-rays, and blood tests for HLA-B27
gene
Psoriatic Arthritis
• Causes pain and swelling in some joints and scaly skin
patches on some areas of the body.
• The symptoms are:
• About 95% of those with psoriatic arthritis have swelling in
joints outside the spine
• Silver or grey scaly spots on the scalp, elbows, knees and/or
lower end of the spine.
• Pain and swelling in one or more joints
• Swelling of fingers/toes that gives them a "sausage"
appearance.
Degenerative Joint Disease
(Osteoarthritis)
• is characterized by progressive loss of cartilage and
reactive changes at the margins of the joint and in the
subchondral bone
• The disease usually begins in one’s 40s
• Prevalence increases with age and the disease
becomes almost universal in individuals aged 65 and
older
• Primarily affects weight-bearing joints such as the
knees, hips, and lumbrosacral spine
Degenerative Joint Disease
• In early disease, pain occurs only after
joint use and is relieved by rest
• As the disease progresses, pain occurs
with minimal motion or even at rest
• Nocturnal pain is commonly associated
with severe disease
Jennifer Morgan, and Terence Partridge Dis. Model. Mech.
2020;13:dmm042192
© 2020. Published by The Company of Biologists Ltd
Muscles
DUCHENNE MUSCULAR DYSTROPHY
• -linked recessive disorder, sometimes also called pseudohypertrophic
muscular dystrophy
• incidence of ~1 per 5200 live-born males
• by age 5 years, muscle weakness is obvious by muscle testing
• muscle biopsy shows muscle fibers of varying size as well as small
groups of necrotic and regenerating fibers
• connective tissue and fat replace lost muscle fibers
• caused by a mutation of the gene that encodes dystrophin,
Dystrophin
• a 427-kDa protein localized to the inner surface
of the sarcolemma of the muscle fiber
• dystrophin gene is >2000 kb in size and thus is
one of the largest identified human genes
• localized to the short arm of the X
chromosome at Xp21.
• the most common gene mutation is a deletion
• the size varies but does not correlate with
disease severity
BECKER MUSCULAR DYSTROPHY
• less severe form of X-linked recessive muscular dystrophy results from allelic defects of
the same gene responsible for Duchenne dystrophy.
• Becker muscular dystrophy is ~10 times less frequent than Duchenne
• proximal muscles, especially of the lower extremities, are prominently involved
• as the disease progresses, weakness becomes more generalized
• mental retardation may occur in Becker dystrophy, but it is not as common as in
Duchenne
• Genetic testing reveals deletions or duplications of the dystrophin gene in 65% of
patients with Becker dystrophy
• in ~95% of patients with Becker dystrophy, the DNA deletion does not alter the
translational reading frame of messenger RNA. These “in-frame” mutations allow
production of some dystrophin
Muscular dystrophy associated proteins
• emerin and lamin A/C are constituents
of the inner nuclear membrane.
Several dystrophy-associated proteins
are represented in the sarcomere
including titin, nebulin, calpain,
telethonin, actinin, and myotilin