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How is the development of enthesopathy associated
with musculoskeletal pathology?
Introduction
Enthesopathy refers to disorders concerning the attachment area of
ligaments or tendons to bones
...

The former, mainly composed of dense fibrous tissue, involves direct
ligament/tendon to bone attachment
...
These fibrocartilaginous
entheses are more common in our joints than fibrous insertions and are
also more susceptible to damage (Apostolakos et al
...
Along with
other connective tissue (made up of collagen and proteoglycans),
Sharpey’s fibres, mainly composed of type I collagen, are key to
connecting tendons and ligaments to the periosteum (Parmar, 2018)
...
, 2010)
...
Common causes of
damage include mechanical overuse, genetic factors and autoimmune
diseases
...

Especially as efficient regeneration does not naturally occur upon
damage to the enthesis (Parmar, 2018)
...

In order to enhance our understanding of enthesopathy, novel recording
methods such as the “Coimbra method” for scoring fibrocartilage layer
changes have been devised (Henderson et al
...
This can prove
useful for efficient identification and diagnosis of different
musculoskeletal conditions when combined with the use of imaging
techniques (e
...
MRI, ultrasound & PET)
...
In turn, this could guide
improved, more personalised treatment for these debilitating conditions
...
This loss of cartilage restricts the space
between the joints and can result in the painful complication of joints
rubbing against each other
...
, 1997)
...
, 2002)
...
Upon closer inspection, other
evolving factors at the enthesis like subchondral bone marrow lesions
(BML) and osteophyte/enthesophyte formation also play a critical role in
OA progression, although it is still unclear if these changes precede
cartilage degradation or not (Felson & Neogi, 2004)
...
in a study of 60 OA patients, during the
earlier stages of OA, subchondral bone tends to remodel in response to
microfractures causing BML development in “74% of tibial plateaus”
...
, 2016)
...


Figure 1: Table summarising the difference between tibial plateaus with BMLs
and those without
...
Compared to the bones without
BMLs, the bones with BMLs had decreased cartilage volume (by 0
...
3) (Muratovic et al
...


Broadly categorised as enthesitis, inflammation of entheses also
appears to be strongly linked to disease progression
...
Consequently, joint oedema,
particularly within the subchondral bone marrow, is also seen as a likely
indication of the presence of these autoimmune conditions (Bredella et
al
...


How the genetics and molecular pathways of enthesopathy are
associated with certain musculoskeletal pathologies
The role of genetic causes in enthesopathy is currently being elucidated
through exploration of several key pathways and expressed genes
...
recently conducted a study showing
transforming growth factor beta (TGF-β) being constantly activated in
enthesopathic mouse models
...
In this case, high concentrations of active
TGF-β led to bone deterioration and fibrocartilage calcification in mouse
tendons as a consequence of excessive mesenchymal stem cell (MSC)
recruitment
...
In these entheses, the fibrocartilage consisted of greater
proteoglycan but decreased collagen content
...
So, it seems increased concentrations of active TGF-β in the
enthesis can trigger fibrocartilage degradation and enthesophyte
formation (Wang et al
...

While the negative effects of TGF- β are generally agreed upon, TGF- β
is still an essential aspect of normal joint metabolism as recent studies
have interestingly pointed out its part in regulating chondrocyte
differentiation during joint stress (Madej et al, 2016)
...


Figure 2: Diagram showing the signalling pathway of TGF- β in bone
...
The
active growth factor then binds to its receptors to initiate the Smad signalling
pathways as well as a Smad independent pathway
...


Meanwhile, good progress has also been made in understanding the
genetics and mechanisms behind spondyloarthropathies like AS
...
Around 90% of AS patients (from different
ethnic groups) have the HLA-B27 gene that encodes for this class I
antigen
...
, 2017)
...
, 2000)
...
IL-17 has even shown involvement in both cartilage and bone
degradation (Chabaud et al
...

However, Felson & Neogi hypothesised that ossification could instead
be connected to imbalanced pyrophosphate levels from a PC‐1
deficiency/mutation
...


Figure 3: Diagram showing the types of inflammatory mediators that may
affect the enthesis
...


Furthermore, a protein known as Annexin A5 (Anxa5), frequently used
as a marker for apoptosis after binding to phosphatidylserine, may play a
critical part in preventing excessive bone growth at the enthesis
...
found that mice deficient of the Anxa5 protein had larger
bone outgrowths at the enthesis after 7 weeks
...
Part of the TGF-β superfamily, BMPs have
shown to potentially trigger excessive bone/osteophyte formation leading
to the ossification seen in AS (Rik et al
...
So, initiated by elevated
TGF-β and BMP levels, accelerated osteophyte formation is
characteristic of OA and AS
...
These data suggest that there is a negative
correlation between Anxa5 and bone overgrowth and mineralisation at
the enthesis
...


Figure 4: Diagram of potential Anxa5 action at the enthesis
...


Assessing entheseal changes using the Coimbra Method and imaging
techniques
Recognising ageing as a factor determining entheseal changes,
Henderson et al
...
After dividing the enthesis
into two major zones, they look to score them according to the type of
changes taking place, namely new bone formation or degradation
...
, 2016)
...
Over the years, improvements in these
techniques has also helped with more precise classification of diseases
affecting the joints
...
, 2016)
...
Lately whole-body MRI scanning is also becoming
popular and can be used very effectively in giving a good overview of the
body’s joints (Poggenborg et al
...
However, more focussed and
precise imaging is needed to visualise the enthesis, which is why fat
saturation (as depicted in Figure 5) and contrast enhancement have
majorly advanced MRI
...
These MRI images
(with B being a fat saturated image), both illustrate synovial inflammation and tendon
thickening (pointed out by the arrows) (Watad et al
...


Discussion/Conclusion
Overall enthesopathy is a complex and occasionally poorly understood
topic
...
It seems that particular
genetic expression and molecular pathways along with other causes like
biomechanical overuse, are closely involved in enthesopathy
progression
...
highlighted
progressive cartilage degradation and subchondral bone lesions as
central pathological features of OA, while enthesis inflammation,
particularly synovitis, is seen in pathologies like AS and rheumatoid
arthritis
...
Conversely, a major limitation
of the genetic studies is the use of animal models (mice in most cases)
to predict enthesopathy development in humans
...
Another limiting factor is the relatively small
sample sizes of these experiments
...
As a result,
without data from large human clinical studies, it would be very difficult
to encompass the several different causative factors and in turn assess
the actual impact and interactions of such molecular pathways
...
However, the
Coimbra method has its own limitations
...
Thus, in conjunction with the
Coimbra method, the simultaneous use of enhanced imaging techniques
and reliable biomarkers would be more reliable for evaluating the type
and extent the extent of entheseal damage
...
Although MRI is comparatively expensive, its accuracy and
ability to clearly depict inflammation at the enthesis has kept it at the
forefront of imaging techniques
...
g
...

To conclude, enthesopathy and musculoskeletal pathology seem to be
closely linked
...
The studies on TGF- β, Annexin A5,
TNF-alpha and interleukins have proven to be promising in uncovering
some of the molecular mechanisms contributing to enthesis damage
...


References



Apostolakos, J
...
J
...
R
...
P
...
H
...
; Beitzel, K
...
B
...
P
...
D
...
333-342
https://www
...
nlm
...
gov/pmc/articles/PMC4241425/



Bredella, M
...
; Steinbach, L
...
; Morgan, S
...
; Davis, J
...
(2006)
“MRI of the Sacroiliac Joints in Patients with Moderate to Severe Ankylosing
Spondylitis”, American Journal of Roentgenology, 187, pp
...
; Watad, A
...
J
...
(2018)
“Spondyloarthritis: new insights into clinical aspects, translational immunology
and therapeutics”, Current Opinion in Rheumatology, 30(5), pp
...
lww
...
12
...
; Lubberts, E
...
; van Den Berg, W
...
(2001)
“IL-17 derived from juxta-articular bone and synovium contributes to joint
degradation in rheumatoid arthritis”, Arthritis Research, 3(3), pp
...
ncbi
...
nih
...
J
...
; Godinez, F
...
; Shelton, D
...
; Hunter,
J
...
; Naguwa, S
...
; Boone, J
...
; Raychaudhuri, S
...
; Badawi, R
...
(2016)
“High-resolution 18F-FDG PET/CT for assessing disease activity in
rheumatoid and psoriatic arthritis: findings of a prospective pilot study”, British
Institute of Radiology, 89(1063)
https://www
...
org/doi/full/10
...
20160138



Chen, B
...
; He, C
...
; Tong, W
...
; Xu, W
...
1943–1951
https://www
...
nlm
...
gov/pmc/articles/PMC5364987/



Felson, D
...
(2004) “Osteoarthritis: Is It a Disease of Cartilage or
of Bone?”, Arthritis & Rheumatism, 50(2), pp
...
wiley
...
1002/art
...
Y
...
; Pany-Kucera, D
...
and Wilczak, C
...
925-932
https://onlinelibrary
...
com/doi/10
...
2477



Henderson, C
...
; Mariotti, V
...
; Villotte S
...
A
...
140-149
https://estudogeral
...
pt/bitstream/10316/44430/1/Age%20effects%20Method
ology%20group%20paper%20accepted%20version
...
; Teichmann, J
...
(2000) “Correlation between plasma
TNF-alpha, IGF-1, biochemical markers of bone metabolism, markers of
inflammation/disease activity, and clinical manifestations in ankylosing
spondylitis”, European Journal of Medical Research, 5(12), pp
...
org/abstract/med/11147993



Li, C
...
; Lee, S
...
(2010) “Assessment of Achilles enthesitis in
the spondyloarthropathies by colour Doppler energy ultrasound in the context
of the 'enthesis organ’”, Scandinavian Journal of Rheumatology, 39(2),
pp
...
tandfonline
...
3109/03009740903273197



Lories, R
...
; Derese, I
...
P
...
1571-9
https://www
...
org/articles/view/23738



Madej, W
...
; Blaney Davidson, E
...
; van der Kraan,
P
...
(2016) “Unloading results in rapid loss of TGFβ signaling in articular
cartilage: role of loading-induced TGFβ signaling in maintenance of articular
chondrocyte phenotype?”, Osteoarthritis Cartilage, 24(10), pp
...
ncbi
...
nih
...
; Cicuttini, F
...
; Findlay, D
...
; Otto, S
...
; Humphries, J
...
; Labrinidis, A
...
; Kuliwaba, J
...
54 https://link
...
com/article/10
...
(2018) “Tendon and ligament: basic science, injury and repair”,
Orthopaedics and Trauma, 32(4), pp
...
sciencedirect
...
P
...
; Østergaard, M
...
J
...
M
...
R
...
J
...
823 https://ard
...
com/content/74/5/823



Rogers, J
...
; Dieppe, P
...
85-90
https://ard
...
com/content/annrheumdis/56/2/85
...
pdf


Shimada, A
...
; Arai, Y
...
; Wada, S
...
;
Amizuka, N
...
; Brachvogel, B
...
; Nakashima, K
...
; Ezura, Y
...
(2018) “Annexin A5 Involvement in Bone
Overgrowth at the Enthesis”,
Journal of bone and mineral research : the official journal of the American
Society for Bone and Mineral Research, 33(8), pp
...
onlinelibrary
...
com/doi/full/10
...
3453



Silver, F
...
; Bradica, G
...
(2002) “Elastic energy storage in human
articular cartilage: estimation of the elastic modulus for type II collagen and
changes associated with osteoarthritis”, Matrix Biology, 21(2), pp
...
sciencedirect
...
; Rozenbaum, M
...
; Rosner, I
...
119-126
https://www
...
com/science/article/pii/S0049017207000108



Van der Kraan, P
...
(2018) “Differential Role of Transforming Growth Factorbeta in an Osteoarthritic or a Healthy Joint”, J Bone Metab, 25(2), pp
...
ncbi
...
nih
...
; Xie, L
...
; Zhen, G
...
; Yang, P
...
; Deng, R
...
; Jia, X
...
; Wan, M
...
(2018) “Aberrant TGF-beta
activation in bone tendon insertion induces enthesopathy-like disease”,
Journal of Clinical Investigation, 128(2), pp
...
ncbi
...
nih
...
; Eshed, I
...
(2017) “Lessons Learned from Imaging
on Enthesitis in Psoriatic Arthritis”, The Israel Medical Association Journal,
19(11), pp
...
ima
...
il/FilesUpload/IMAJ/0/262/131048
...
; Chen, G
...
(2016) “TGF-β and BMP signaling in osteoblast,
skeletal development, and bone formation, homeostasis and disease”, Bone
Research, 4, article no
...
nature

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