EDITORIAL
published: 27 July 2021
doi: 10.3389/ med.2021.727700
F on ie s in Medicine | www. on ie sin.o g 1July 2021 | Volume 8 | A icle 727700
Edi ed and e iewed by:
Ying Ying Leung,
Singapo e Gene al
Hospi al, Singapo e
*Co espondence:
Ali Mobashe i
[email p o ec ed]
†ORCID:
Ali Mobashe i
o cid.o g/0000-0001-6261-1286
João Eu ico Fonseca
o cid.o g/0000-0003-1432-3671
O es e Gualillo
o cid.o g/0000-0002-7154-1328
Y es Hen o in
o cid.o g/0000-0002-2846-4398
Raquel La go
o cid.o g/0000-0001-6525-2944
Gab iel He e o-Beaumon
o cid.o g/0000-0002-3241-991X
F ancisco Ai on Cas o Rocha
o cid.o g/0000-0003-4370-3294
Special y sec ion:
This a icle was submi ed o
Rheuma ology,
a sec ion o he jou nal
F on ie s in Medicine
Recei ed: 19 June 2021
Accep ed: 30 June 2021
Published: 27 July 2021
Ci a ion:
Mobashe i A, Fonseca JE, Gualillo O,
Hen o in Y, La go R,
He e o-Beaumon G and Rocha FAC
(2021) Edi o ial: In lamma ion and
Bioma ke s in Os eoa h i is.
F on . Med. 8:727700.
doi: 10.3389/ med.2021.727700
Edi o ial: In lamma ion and
Bioma ke s in Os eoa h i is
Ali Mobashe i1,2,3,4,5*†, João Eu ico Fonseca 6,7†, O es e Gualillo8†, Y es Hen o in9,10†,
Raquel La go11†, Gab iel He e o-Beaumon 11† and F ancisco Ai on Cas o Rocha12†
1Resea ch Uni o Medical Imaging, Physics and Technology, Facul y o Medicine, Uni e si y o Oulu, Oulu, Finland,
2Depa men o Regene a i e Medicine, S a e Resea ch Ins i u e Cen e o Inno a i e Medicine, Vilnius, Li huania,
3Depa men s o O hopedics, Rheuma ology and Clinical Immunology, Uni e si y Medical Cen e U ech , U ech ,
Ne he lands, 4Depa men o Join Su ge y, Fi s A ilia ed Hospi al o Sun Ya -sen Uni e si y, Guangzhou, China, 5Wo ld
Heal h O ganiza ion Collabo a ing Cen e o Public Heal h Aspec s o Musculoskele al Heal h and Aging, Uni e si y o Liège,
Liège, Belgium, 6Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de Lisboa,
Lisbon, Po ugal, 7Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e
(CHULN), Lisbon Academic Medical Cen e, Lisbon, Po ugal, 8SERGAS (Se izo Galego de Saude) and IDIS (Ins i u o de
In es igación Sani a ia de San iago), NEIRID Lab (Neu oendoc ine In e ac ions in Rheuma ology and In lamma o y Diseases),
Resea ch Labo a o y 9, San iago Uni e si y Clinical Hospi al, San iago de Compos ela, Spain, 9MusculoSKele al Inno a i e
Resea ch Lab (mSKIL), A h opole Liège, Depa men o Mo ici y Sciences, Cen e o In e disciplina y Resea ch on
Medicines (CIRM), Uni e si y o Liège, CHU Sa -Tilman, Liège, Belgium, 10 Physical The apy and Rehabili a ion Depa men ,
P incess Paola Hospi al, Ma che-En-Famenne, Belgium, 11 Bone and Join Resea ch Uni , Rheuma ology Depa men ,
IIS-Fundación Jimenez Diaz UAM, Mad id, Spain, 12 Depa men o In e nal Medicine, Faculdade de Medicina da
Uni e sidade Fede al do Cea á, Fo aleza, B azil
Keywo ds: os eoa h i is, bioma ke s, ca ilage, syno ium, in lamma ion
Edi o ial on he Resea ch Topic
In lamma ion and Bioma ke s in Os eoa h i is
Os eoa h i is (OA) is he mos common o m o a h i is a ec ing mo e han 500 million people
globally (1). I accoun s o mo e pain and unc ional disabili y han any o he musculoskele al
disease and is an impo an sou ce o high socie al and economic cos s (2). Al hough he
pa hophysiology o OA is poo ly unde s ood (3), he isk ac o s associa ed wi h disease
de elopmen a e well-es ablished. They include age (4), obesi y (5), sex (6), p e ious incidence o
join inju ies (7,8), meniscal damage (9), join ins abili y (10), malalignmen (11), gene ics (12),
bone shape (including ana omical de o mi ies) (13), muscle weakness and sa copenia (14), and
me abolic disease (15–17). Al hough OA can a ec any syno ial join , including join s in he hand,
acco ding o s udies on he global bu den o disease in 2010 (18) and 2017 (19), knee OA ep esen s
he g ea es socie al bu den.
Beside mechanical de angemen , in lamma ion plays a key ole in he pa hogenesis and
p og ession o OA (20,21). Howe e , he in lamma ion associa ed wi h OA is no he same ype and
g ade ha is associa ed wi h heuma oid a h i is (RA) and o he in lamma o y diseases o join s
(22). I is becoming inc easingly accep ed ha “low-g ade” in lamma ion and he mechanisms ha
egula e i a e ele an no only o join pain and disabili y in OA (23), bu also o join auma and
he biomechanical damage sus ained o join issues (24–26). Pe sis en syno i is as well as damage
o he subchond al bone ha e been conside ed o play majo oles in join des uc ion, pa icula ly
in knee OA (27,28). The associa ion o meniscal damage wi h OA p og ession has highligh ed he
ole o he meniscus and i s biomechanical ole in he join (29–31). The e o e, he menisci may
also pa icipa e in he in lamma o y scena io o join s a ec ed by OA (32).
Ano he impo an con ibu o o he p ocess o “low-g ade” in lamma ion in OA is he
syno ium (23,33). The e is e idence o c oss- alk be ween a icula ca ilage, subchond al bone
and syno ium. Mechanis ic e idence comes om in i o and animal s udies and clinical e idence
Mobashe i e al. Edi o ial: In lamma ion and Bioma ke s in Os eoa h i is
om s udies on pa ien s wi h OA (34,35). Syno ial cells,
pa icula ly ype A mac ophage-like syno iocy es, a e likely o
be he majo sou ce o p o-in lamma o y media o s wi hin he
join (36). Mo eo e , he e a e di e ences in he p o ile o
p o-in lamma o y cy okine p oduc ion in classically ac i a ed
(M1) and al e na i ely ac i a ed (M2) mac ophages (37,38).
Mac ophage pola isa ion is an issue ha may be ele an no only
o eme ging a ge ed he apies bu also o ongoing e o s aimed
a disc imina ing he di e en molecula endo ypes and clinical
pheno ypes o OA (39,40).
Biochemical ma ke s (also called molecula ma ke s,
signa u e molecules o bioma ke s) a e biological molecules
ound in body luids, o issues ha may be used as indica o s
o physiological and pa hophysiological p ocesses. They can
be de ined as “a cha ac e is ic ha is objec i ely measu ed and
e alua ed as an indica o o no mal biological p ocesses,
pa hogenic p ocesses, o pha macologic esponses o a
he apeu ic in e en ion.” (41). Bioma ke s may be used
o see how well pa ien s espond o new ea men s and
in e en ions o a disease o condi ion. In OA bioma ke s may
be used o unde s and disease pa hogenesis, s udy p og ession
and de ine he molecula endo ypes (42,43). Bioma ke s ha e
been used e y e ec i ely o iden i y molecula endo ypes and
clinical pheno ypes in o he disease a eas. Fo example, in
as hma, bioma ke s ha e been used o iden i y pheno ypes and
endo ypes ha cha ac e ise se e e as hma (44,45). Howe e , in
he ield o OA we a e lagging behind and need o ca ch up in
o de o enhance clinical ials and acili a e d ug de elopmen .
Bioma ke s o ea ly OA ep esen a majo unme need and
mo e esea ch needs o be done o iden i y bioma ke s ha
cha ac e ise ea ly e en s in he pa hogenesis o OA.
The aim o his Resea ch Topic was o assemble a
comp ehensi e collec ion o au ho i a i e a icles ocusing on
undamen als o he in lamma o y scena io in OA join s
and hei ele ance o exis ing and eme ging bioma ke s in
his disease. One o he key p io i ies is he iden i ica ion,
cha ac e isa ion and alida ion o bioma ke s ha de ine
molecula endo ypes o OA, se ing as ools o disc imina e
di e en OA pheno ypes.
Mic oRNAs (miRNAs) a e pos - ansc ip ional egula o s ha
a e dys egula ed in os eoa h i ic issues including he syno ium.
miRNAs a e impo an con ibu o s o OA syno ial changes and
o ac as no el he apeu ic a ge s. Ta allaee e al., e iewed he
ecen ly published li e a u e in es iga ing he oles ha miRNAs
play in OA- ela ed syno ial pa hologies including in lamma ion,
ma ix deposi ion and cell p oli e a ion. Thei analysis o he
li e a u e has e ealed ha miRNAs con ibu e o syno ial
homeos asis, in lamma ion, ib osis, angiogenesis, cell su i al
and cell apop osis, con ibu ing o OA syno ial pa hology.
The in lamma ion uelled by me abolic imbalance, also known
as “me a-in lamma ion,” is a ype o ch onic (long-las ing),
pe sis en bu “low-g ade” sys emic in lamma ion caused by
mul iple componen s in ol ed in me abolic synd ome (Me S),
including cen al obesi y, adipokine dys egula ion, and impai ed
glucose ole ance. G a al e al., e iewed he li e a u e ocusing
on pu ine gic egula ion in OA ca ilage and how di e en
componen s o Me S modula e he pu ine gic sys em in OA.
They desc ibed he c i ical ole o ecep o s, such as adenosine
A2A ecep o (A2AR) and ATP P2X7 ecep o in OA and assess
how nucleo ides egula e he in lammasome in OA.
Villal illa e al. conduc ed an animal s udy using abbi s o
in es iga e he e ec o hype choles e olemia induced by high-
a die (HFD) in ca ilage om OA abbi s, and how oxLDL
a ec human chond ocy e in lamma o y and ca abolic esponses.
They ound ha HFD in ake does no modi y ca ilage s uc u e
o p o-in lamma o y and ca abolic gene exp ession and p o ein
p esence, bo h in heal hy and OA animals. Thei s udy concluded
ha die a y choles e ol in ake may no be dele e ious o a icula
ca ilage bu al e ed choles e ol me abolism may be in ol ed in
he associa ions obse ed in human disease.
Al hough bioma ke s a e impo an in OA esea ch, clinical
ials, and d ug de elopmen , hey ha e no ye had any
signi ican impac on he clinical managemen o he OA
and ollow-up. Be no iene e al., a gued ha eme ging nano-
echnologies and immunoassay pla o ms ha a e al eady
impac ing on ou ine diagnos ics and moni o ing in o he
diseases could po en ially se e as echnological and s a egic
examples o enhanced clinical managemen o OA. Thei e iew
a icle explo ed he implemen a ion o such echnologies in
OA esea ch and he apy and discussed he challenges ha
hinde he de elopmen , es ing, and implemen a ion o new
OA biochemical ma ke assays u ilising eme ging mul iplexing
echnologies and biosenso s.
Rajand an e al., e alua ed he associa ion be ween
bioma ke s o inna e immuni y and magne ic esonance
imaging (MRI) ea u es o ea ly and la e s ages o knee
OA. They in es iga ed bioma ke s o inna e immuni y
associa ed wi h meniscal ex usion and syno ial in lamma ion
in ea lie s age and bone ma ow lesions (BMLs) in la e
s ages o knee OA. They also obse ed associa ions be ween
p o-in lamma o y bioma ke s and a ious MRI ea u es
in he ea ly s ages o knee OA. Thei explo a o y s udy
suppo ed he associa ion be ween bioma ke s o ac i a ed
mac ophages and syno ial in lamma ion in he ea ly s ages o
knee OA.
Lambe e al., e iewed he li e a u e ocusing on damage-
associa ed molecula pa e ns (DAMPs) as bioma ke s and
po en ial he apeu ic a ge s o OA. Thei pape highligh ed
he cen al ole o DAMPs in he in e play be ween immune
esponses and in lamma ion in OA.
Sun e al., used a a model o OA o de e mine whe he
swi ching om an obesogenic die o a no mal chow
die can mi iga e he de imen al e ec s o in lamma o y
pa hways ha con ibu e o OA pa hology. Thei esul s
indica ed ha die a y swi ching om an obesogenic die o
a no mal die educes body weigh and es o es me abolic
pa ame e s and supp esses syno ial in lamma ion. They
concluded ha obesogenic die s induce sys emic and
syno ial in lamma ion and die a y swi ching may be
used as an in e en ion o slow down he p og ession
o OA.
Wo k by de Melo Nunes e al. examined he chemical
composi ion o glycosaminoglycans (GAGs) om no mal and
os eoa h i ic ca ilage and a epo ed educed sulphu con en
F on ie s in Medicine | www. on ie sin.o g 2July 2021 | Volume 8 | A icle 727700
Mobashe i e al. Edi o ial: In lamma ion and Bioma ke s in Os eoa h i is
in GAGs om OA pa ien s, which is associa ed wi h a educed
ze a po en ial.
Finally, Zhang e al., e iewed he li e a u e on syno ial
ib osis in OA, es ablishing he concep ha ib osis is an e en ual
ou come o in lamma ion in OA. The e o e, new in e en ions
a e needed o slow he p og ession o ib osis in OA and
associa ed co-mo bidi ies. They p oposed he combined use o
an i- ib o ic d ugs wi h po en ial o he apy in OA.
We hope ha you enjoyed eading hese pape s as much as we
enjoyed edi ing hem o his Resea ch Topic in he heuma ology
sec ion o F on ie s in Medicine.
AUTHOR CONTRIBUTIONS
All au ho s con ibu ed o he w i ing, edi ing, and e ision o
his edi o ial.
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F on ie s in Medicine | www. on ie sin.o g 4July 2021 | Volume 8 | A icle 727700