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
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
Energy metabolism of osteocytes
• unique hypoxic environment
• autophagy in the osteocyte
• has been shown to be crucial to regulate secondary
mineralization
Current Osteoporosis Reports volume 19, pages444–451 (2021)
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.
• 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.
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 .
Other 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
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
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
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.
Not only osteoclasts formation
Sclerostin acts on mesenchymal
stem cell precursors and promotes
bone marrow adipogenesis
Wnt antagonists Dkk-1 and
Sclerostin produced by osteocytes
inhibit osteoblast differentiation
and bone forming function
Sclerostin levels positively correlate
with body and fat mass in healthy
adults and diabetic patients
DELGADO-CALLE AND BELLIDO, 2022,Physiol Rev102: 379–410August 2, 2021; Published by the American Physiological Society.
Therapeutics targeting
Antibodies to neutralize
Sclerostin and Dkk1
(clinically tested but not FDA
approved)
antibody against RANKL
(clinically tested and FDA
approved)
…..
DELGADO-CALLE AND BELLIDO, 2022,Physiol Rev102: 379–410August 2, 2021; Published by the American Physiological Society.
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.
Effects of PTHrP
Cell growth, differentiation and apoptosis in many fetal
and adult tissues. In the absence of PTHrP there is a
reduction in chondrocyte proliferation with emphasis on
chondrocyte differentiation and apoptosis
Normal development of cartilaginous growth plate. In the
fetal period, PTH plays a dominant anabolic role in
trabecular bone development. PTHrP regulates growth plate
development.
Postnatally, PTHrP, as a paracrine/autocrine regulator,
assumes an anabolic role for bone homeostasis, whereas
PTH primarily maintains Ca ++ levels in the ECT through
bone resorption.
Development 2008 135: 1947-1956
+ others
DELGADO-CALLE AND BELLIDO, 2022,Physiol Rev102: 379–410August 2, 2021; Published by the American Physiological Society.
Gene Mutation Disease
RANK
18 bp duplication Familial expansile osteolysis
27 bp duplication Early onset Paget’s disease
15 bp duplication
Expansile skeletal
hyperphosphatasi
a
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
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.
Pathologic Fractures
• Tumors
• primary
• secondary (metastatic) (most common)
• Metabolic
• osteoporosis (most common)
• Paget’s disease
• hyperparathyroidism
!
Pathological fracture in pediatric patient
• a fracture associated with
• minimal trauma
• location of the fracture is unusual
• abnormal process in the bone is seen in the radiographs
• cause of changes to the normal biomechanics of bone
• Intrinsic processes
• bone tumours (both benign and malignant),
• metabolic diseases
• osteogenesis imperfecta,
• infection
• extrinsic processes
• internal fixation,
• biopsy tracts and
• radiation
Common predisposing benign and malignant lesions by age (adapted with permission from Arkader A, Dormans JP. Pathologic fractures associated with tumors
and unique conditions of the musculoskeletal system. In: Beaty JH, Skaggs DL, Flynn JM, Waters K, eds. Rockwood and Wilkins’ fractures in children. Seventh ed.
Philadelphia: Lippincott Williams & Wilkins, 2010:120–191)
Age (yrs) Benign lesions Malignant lesions
0 to 5 Osteomyelitis
Metastatic tumours (neuroblastoma, Wilm’s
tumour)
Eosinophilic granuloma Leukaemia
Hand-Schuller-Christian disease Ewing sarcoma
Fibrosarcoma
Eosinophilic granuloma/ Letterer-Siwe disease
5 to 10 Unicameral bone cyst (UBC) Leukaemia
Aneurysmal bone cyst (ABC) Osteogenic sarcoma
Nonossifying fibroma (NOF) Ewing sarcoma
Osteochondroma
Fibrous dysplasia
Enchondroma/Ollier disease
Neurofibromatosis/Congenital pseudarthrosis of the
tibia
10 to 20 Unicameral bone cyst Leukaemia
Aneurysmal bone cyst Lymphoma
Nonossifying fibroma Osteogenic sarcoma
Osteochondroma Ewing sarcoma
Fibrous dysplasia
Chondroblastoma
Giant cell tumour
Osteoid osteoma
Bone remodelling defects
• Osteoporosis
• Osteodystrophy
• Rachitis/osteomalacia
• Paget`s disease
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.
• Caucasin population: about 50% of women and 20% of men older than 50 years
will have a fragility fracture in their remaining lifetime.
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.
The World Health Organization (WHO) uses T-scores to
define normal bone mass, low bone mass (or
osteopenia), and osteoporosis. The T-score compares
bone density to the average bone density of young
healthy adults of same gender.
Osteoporosis - causes
• Estrogene deficiency
• Glucocorticoids excess
• Vitamin K2 deficiency
• Immobilization
Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013.
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
• An increase in bone resorption, and not
impaired bone formation
• 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
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 agerelated
fracture risk, although the relative risk
of fracture related to glucocorticoid use may
be even higher in patients under 65. Nature Reviews Rheumatology volume 6, pages82–88 (2010)
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) and 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…
Dermato-endocrinology, 01 Jan 2014, 6(1):e968490
Vitamin K dependent Gla protein Function
Liver Hepatic carboxylation
Clotting factors II, VII, X and XII Haemostasis (procoagulant activity)
Protein C, S and Z Haemostasi (anticoagulant activity)
Various tissues Extra hepatic carboxylation
Osteocalcin Calcium and bone metabolism
Matrix-Gla-Protein
Inhibitor of vascular calcification (cartilaginous tissue, vascular wall of the
vascular smooth muscle cells)
Growth-arrest specific gene 6 (Gas6)
Cell growth (endothelium, smooth muscle cells), apoptosis, phagocytosis
(?)
Transmembrane GLA-protein Signal transduction to phosphatidylserine (?)
Periostin Bone metabolism, cell migration, angiogenesis (?)
Other: carboxylase, transthyretin, Gla-rich-Protein (GRP) To date mainly unknown
Osteocalcin (OCN)
• the most abundant non-collagen bone matrix protein
• has been widely used as a biochemical serum marker
of bone formation
• a hormone that regulates glucose homeostasis,
energy expenditure, male fertility, brain
development, and cognition.
• OCN is regulated by insulin signaling in OBs and, in a
feed-forward loop,
• OCN stimulates pancreatic β-cell proliferation and
insulin secretion and improves insulin sensitivity in
peripheral tissues.
• newly assigned metabolic role for the skeleton raises
important questions as to the normal physiological
and pathophysiological regulation of glucose
metabolism by the skeleton J Cell Physiol.2018;233:3769–3783.
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.
J Cell Physiol.2018;233:3769–3783.
Sweet bone—osteoporotic fractures in
diabetes mellitus
Impaired osteogenesis in T1DM.
Pancreatic β-cell destruction in
patients with T1DM prevents
secretion of insulin, IAPP and
preptin, thereby reducing their
effects on the RUNX2 gene.
This reduction decreases
proliferation and differentiation of
MSCs into osteoblasts and their
resistance to apoptosis—
preventing osteogenesis and
bone mass
Type 1 diabetes mellitus (T1DM)
affects the skeleton more severely
than type 2 diabetes mellitus (T2DM)
Nature Reviews Endocrinology volume 8, pages297–305 (2012)
DM bone
Current Osteoporosis Reports, 13 (5), 327-335.
T2DM negatively affects trabecular bone mass, while cortical bone mass is increased. (1)
The number and function of bone-forming osteoblast is reduced. In addition, vitamin D
serum levels are decreased, which alters calcium and phosphate homeostasis. (2)
Osteoblasts derive from MSC that favor differentiating into fat-storing adipocytes in T2DM
leading to bone marrow adiposity and increased expression of cytokines and chemokines
as well as to an elevated amount of free unsaturated fatty acids. (3) This results in
increased inflammation leading to accumulation of pro-inflammatory M1 macrophages and
reduced switch into anti-inflammatory M2 macrophages. (4) The network of osteocytes is
reduced due to an increased apoptosis rate. They increase their expression of sclerostin,
an inhibitor of osteoblast function, and RANKL, a promoter of osteoclastogensis. FGF-23, a
phosphaturic hormone, is additionally increased. (5) Effects on osteoclasts are
controversial in the literature, but T2DM is generally accepted to reduce bone turnover and
thus also osteoclast function. (6) The amount of endothelial progenitor cells (EPC) is
reduced in T2DM leading to vessel permeability. In addition, T2DM causes microhypoxia in
bone niche, which in turn increases inflammation. (7) T2DM patients have an increased risk
of falls and fractures due to reduced bone quality indicated by (8) an increased formation of
advanced glycation end-products (AGEs) and (9) cortical porosity.
Endocrine Connections 2019; 8, 3; 10.1530/EC-18-0456
Nature Reviews Endocrinology volume 15, pages33395–355(2019)
Bone remodelling defects
• Osteoporosis
• Osteodystrophy
• Rachitis/osteomalacia
• Paget`s disease
• Rare diseases
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;
Bone remodelling defects
• Osteoporosis
• Osteodystrophy
• Rachitis/osteomalacia
• Paget`s disease
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.
• 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.
Bone remodelling defects
• Osteoporosis
• Osteodystrophy
• Rachitis/osteomalacia
• Paget`s disease
Gene Mutation Disease
RANK
18 bp duplication Familial expansile osteolysis
27 bp duplication Early onset Paget’s disease
15 bp duplication
Expansile skeletal
hyperphosphatasi
a
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
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 TNFRSF11Afor 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
Bone remodelling defects
• Osteoporosis
• Osteodystrophy
• Rachitis/osteomalacia
• Paget`s disease
• Rare diseases
Osteopetrosis
• a rare genetic bone disorder caused by a
malfunction of the osteoclasts that leads to
increased bone density.
• The three primary types are
• autosomal recessive osteopetrosis,
• intermediate autosomal recessive osteopetrosis,
• and autosomal dominant osteopetrosis.
• Autosomal dominant osteopetrosis is the most
frequent and less severe type, begins in
adolescence, predominantly affects the axial
skeleton and the long bones symmetrically, and
is accompanied by an increased fracture rate due
to the instability of affected bone.
• Autosomal dominant osteopetrosis has a general
worldwide prevalence of one in 20 000 births.
Neolithic individual with osteopetrosis and the
diagnostic methods applied
Bones showed a marked, generalised sclerosis with obliteration
of the medullary cavity. They were remarkable for their heavy
weight. A distinct characteristic of osteopetrosis is the flaring of the
metaphyses in long bones.
www.thelancet.com/diabetes-endocrinology Vol 8 October 2020
Osteopetrosis
• a rare genetic bone disorder caused by a
malfunction of the osteoclasts that leads to
increased bone density.
• The three primary types are
• autosomal recessive osteopetrosis,
• intermediate autosomal recessive osteopetrosis,
• and autosomal dominant osteopetrosis.
• Autosomal dominant osteopetrosis is the most
frequent and less severe type, begins in
adolescence, predominantly affects the axial
skeleton and the long bones symmetrically, and
is accompanied by an increased fracture rate due
to the instability of affected bone.
• Autosomal dominant osteopetrosis has a general
worldwide prevalence of one in 20 000 births.
Neolithic individual with osteopetrosis and the
diagnostic methods applied
Bones showed a marked, generalised sclerosis with obliteration
of the medullary cavity. They were remarkable for their heavy
weight. A distinct characteristic of osteopetrosis is the flaring of the
metaphyses in long bones.
www.thelancet.com/diabetes-endocrinology Vol 8 October 2020
Collagen abnormalities
AD osteogenesis imperfecta bone dysplasia:
Mutations in either COL1A1 or COL1A2 are translated into collagen αchains
with abnormal structure, which delay folding of the
heterotrimer and result in excess post-translational modification of
the collagen helical region.
Mutant procollagen chains unable to incorporate into heterotrimers
are
• retrotranslocated into the cytosol and degraded by the ERAD
pathway (1);
• fully misfolded heterotrimers with structural defects generate
supramolecular aggregates that are eliminated by autophagy (2);
• mutant molecules with triple helical mutations are degraded
through an unidentified pathway (3).
• abnormal procollagen can be secreted, processed and incorporated
in the extracellular matrix (4).
The secreted mutant collagen affects fibril structure and interactions
of noncollagenous proteins with matrix, as well as matrix
mineralization and osteoblast development and cell–cell and cell–
matrix crosstalk. The overall result is bone deformity and fragility
Nature Reviews Endocrinology 7(9):540-57
Collagen abnormalities
AD osteogenesis imperfecta bone dysplasia:
Mutations in either COL1A1 or COL1A2 are translated into collagen αchains
with abnormal structure, which delay folding of the
heterotrimer and result in excess post-translational modification of
the collagen helical region.
Mutant procollagen chains unable to incorporate into heterotrimers
are
• retrotranslocated into the cytosol and degraded by the ERAD
pathway (1);
• fully misfolded heterotrimers with structural defects generate
supramolecular aggregates that are eliminated by autophagy (2);
• mutant molecules with triple helical mutations are degraded
through an unidentified pathway (3).
• abnormal procollagen can be secreted, processed and incorporated
in the extracellular matrix (4).
The secreted mutant collagen affects fibril structure and interactions
of noncollagenous proteins with matrix, as well as matrix
mineralization and osteoblast development and cell–cell and cell–
matrix crosstalk. The overall result is bone deformity and fragility
Nature Reviews Endocrinology 7(9):540-57
Noncollagen genes in which mutations cause
osteogenesis imperfecta variants
Calcified Tissue International 2013
Marfan syndrome
• Fibrillin is the major
component of beaded
microfilaments
possessing elasticity Name M.W. Structure Domains Site of expression Normal function Pathology
Fibrillin-1 ~320 kDa
Extracellular
microfibrils
cbEGF-like, TB,
hybrid domains
Mature skin,
embryonic
tissues, aorta
Proper assembly
of elastic fibers
Marfan,Weill–
Marchesani
syndrome
Fibrillin-2 ~350 kDa
Extracellular
microfibrils
cbEGF-like, TB,
hybrid domains
Developing skin
and other
embryonic
tissues,
developing digits
Proper assembly
of elastic fibers,
bone formation
Mild skin
pathology, Beals
syndrome, distal
arthrogryposis
Fibrillin-3 ~350 kDa
Extracellular
microfibrils
cbEGF-like, TB,
hybrid domains
Embryonictissues
Assembly of
elastic fibers
Unknown
Source: cb EGF-like calcium-binding EGF-like domain, TB TGFβ binding domain.
Abbreviations: cb, calcium binding; EGF, epidermal growth factor; TB, binding sites for TGFβ.Reference Module in Biomedical Sciences, 2017
The Journal of Cell Biology 190(6):949-51
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 IIcollagen,
tendon and bone are composed primarily
of type Icollagen.
Articular diseases
• rheumatoid arthritis (RA) and
• osteoarthritis (OA).
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.
Clinical Presentation of RA
Early RA Intermediate
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 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 progression
• Early Pannus
• Granulation,
inflammation at
synovial membrane,
invades joint, softens
and destroys cartilage
Advanced Pannus
joint cartilage disappears,
underlying bone
destroyed,
surfaces collapse
joint
Fibrous Ankylosis
Fibrous connective tissue
replaces pannus; loss of joint
otion
Bony Ankylosis
Eventual tissue and
joint calcification
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
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)
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.
Articular diseases
• rheumatoid arthritis (RA) and
• osteoarthritis (OA).
Osteoarthritis
• major source of pain, disability, and
socioeconomic cost worldwide
• epidemiology - complex and multifactorial,
with genetic, envirnmental, and
biomechanical components
• characterized by progressive loss of cartilage
and reactive changes at the margins of the
joint and in the subchondral bone
Risk factors for osteoarthritis
• Joint biomechanics are dictated by anatomical and functional factors
• Anatomical factors include joint morphology
• With respect to functional factors, poor quadriceps function
• Sport
• Age
• reduction in regenerative capacity and accumulation of risk factors
• Injury
• Obesity
• load on weight-bearing joints,
• increased joint susceptibility through inflammatory adipokines
• Genetics
Pathogenesis
• Osteoarthritis - once viewed as
a disease of purely mechanical
cartilage degradation,
• but it is now known to be a
complex condition affecting the
whole joint, in which activation
of matrix proteases has a
pivotal role
Cartilage, subchondral bone, and synovium probably all have key
roles in disease pathogenesis, and an association with systemic
inflammation could also be present.
THE LANCET, VOLUME 386, ISSUE 9991, P376-387, JULY 25, 2015
Synovium
• Synovitis is a common feature of osteoarthritis,
even in early disease. In established
osteoarthritis, proliferation of synoviocytes and
tissue hypertrophy are notable, with increased
vascularity.
• Synoviocytes synthesise lubricants such as
hyaluronic acid and lubricin.
• These contribute to optimum joint function but
show reduced lubricating capacity in subsets of
patients with osteoarthritis.
• Synoviocytes, like chondrocytes and
osteoblasts, also release inflammatory
mediators and degradative enzymes.
THE LANCET, VOLUME 386, ISSUE 9991, P376-
387, JULY 25, 2015
Cartilage
• main structural protein - type II collagen, which provides a meshwork
that receives stabilisation from other collagen types and non-collagenous
proteins and provides cartilage with tensile strength.
• Aggrecan and other proteoglycans are embedded within this framework,
and draw water into the cartilage, providing compressive resistance.
• Cartilage architecture and biochemical composition are strictly regulated
by chondrocytes in response to changes
• they produce several inflammatory response proteins, such as cytokines,
including interleukin 1β, interleukin 6, and tumour necrosis factor (TNF) α, and
matrix-degrading enzymes including the metalloproteinases and a disintegrin
and metalloproteinase with thrombospondin-like motifs (ADAMTS).
Subchondral bone
• Subchondral cortical bone forms an interface
between the calcified cartilage below the
tidemark and the underlying trabecular bone.
• Pronounced changes from normal are seen
in the structure and composition of both
the cortical plate and trabecular bone in
osteoarthritis.
• Features of endochondral ossification are
reinitiated in osteoarthritis and the tidemark
advances, with associated vascular penetration.
This process is accompanied by the formation of
osteophytes and subchondral cysts.
Osteoarthritis and Cartilage 22 (2014)
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
Osteonecrosis
• idiopathic or secondary to numerous diseases
• spontaneous occurrences lack an obvious etiology,
• most cases occur secondary to trauma
• non-traumatic has been associated with
• corticosteroid usage,
• alcoholism,
• infection,
• hyperbaric events,
• storage disorders,
• marrow infiltrating diseases,
• coagulation defects
• some autoimmune diseases.
E.g., in trauma, the normal vascular supply to the femoral
head is damaged, leading to ONFH.
Jennifer Morgan, and Terence Partridge Dis. Model. Mech.
2020;13:dmm042192
© 2020. Published by The Company of Biologists Ltd
Muscles
Osteocytes and Skeletal Muscle
• cross talk between bone and
muscle
•
• osteocytes induce acceleration
and inhibition of myogenesis
• Osteokines secreted by osteoblast (OB) and osteocyte
(such as sclerostin, osteocalcin prostaglandin E2,
transforming growth factor-β and receptor activator for
nuclear factor-κ B ligand) affect muscle metabolism
• Myokines secreted by muscle include interleukin and
myostatin. IL-6 regulates OB and osteocyte by binding
to the IL-6 receptor gp130. Myostatins (such as
musclin, irisin, insulin like growth factor-1 and
fibroblast growth factor 2) also affect osteocyte, OB
and osteoclast.
De Gruyter September 15, 2022
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
Sarcopenia
Aging of skeletal muscle is central in the
pathogenesis of immune senescence and
sarcopenia. Multiple pathways are
affected, including insufficient myokine
signalling (IL-6, IL-7, IL-15), shifting of
membrane bound immune regulatory
factors towards a pro-inflammatory
profile, impaired immune cell function
and altered body composition.
eBioMedicine 2019 49381-388DOI: (10.1016/j.ebiom.2019.10.034)
Thank you for your attention