rheumatoid arthritis ( ra ) is the most frequent chronic autoimmune inflammatory rheumatism , with a worldwide prevalence around 1% . ra severity is related to joint destruction characterised by erosion and space narrowing that is responsible for joint functional disability [ 24 ] . early diagnosis and treatment are crucial in order to prevent joint destruction and preserve joint function defining the  window of opportunity  concept [ 5 , 6 ] . since few years , the concept  outside - inside  suggested a beginning of ra disease also in the subchondral bone marrow . in fact , a subchondral bone loss at the metacarpal phalangeal head starts since the early phase of ra disease . furthermore , joint inflammation due to synovitis is one of the most powerful predictors of new bone erosion . so , the synovial membrane was the first actor mainly described by production of some mediators induced by inflammatory cytokines such as tnf or others . these mediators induced cartilage matrix degradation and subchondral bone loss [ 10 , 11 ] . these data support a strong interaction between synovial membrane , cartilage , and subchondral bone . inflammatory joint induced the release of specific protein fragments from its various compartments into the serum and the urine , which may be used as tissue specific biomarkers . by this way , biomarkers of each component of the joint could be useful to manage ra patients . tnf inhibitors and other biologics reduce synovitis , biomarkers of inflammation , and bone destruction . these tnf inhibitors are able to block joint destruction , even if ra disease is still active [ 1315 ] . in 2014 , in front of early ra patient , the goal of early ra therapy is to obtain remission according to the new criteria for remission acr / eular . however , though clinical remission was obtained , in some patients a structural progression can occur   probably due to persistence of joint inflammation [ 18 , 19 ] . exploration with specific biomarkers of each component of the joint could be helpful to investigate this paradigm . in daily practice in 2014 , only das28 combining clinical parameters with erythrocyte sedimentation rate ( esr ) or c - reactive protein ( crp ) is used . so , they are not strongly correlated with joint involvement . despite its large usefulness in daily practice , das28 fails to strongly predict the joint progression or a real remission . at the time of  personalized medicine ,  which aims to individually improve treatment management , biomarkers of the joint will be useful in ra especially at the early stage . the aim of this paper is to review some biomarkers of synovial , cartilage , and bone turnover in ra , clarify their utility in ra management , and analyze data in remission . matrix metalloproteinase-3 ( mmp-3 or stromelysin 1 ) is a proteinase secreted by synovial fibroblasts and chondrocytes . its activity results in degradation of aggrecan core protein , cartilage link protein , fibronectin , and collagen types iv , vii , ix , and xi . mmp-3 is present in ra synovial fluid and overexpressed in rheumatoid synovium [ 23 , 24 ] . one mmp-3 polymorphism was described to be associated with higher joint damage in ra [ 25 , 26 ] . otherwise , serum mmp-3 level was suggested as a predictor for joint destruction in early ra [ 27 , 28 ] or established ra [ 29 , 30 ] . correlation between serum mmp-3 level and joint damage progression appeared to be independent of rheumatoid factor ( rf ) or acpa status . the next step was to assess mmp-3 variation induced by ra therapy and particularly during biological therapies . anti - tnf therapy decreased mmp-3 expression in ra patients [ 32 , 33 ] . similar results were observed with tocilizumab ( il-6 blocker )   or abatacept ( inhibitor of costimulation ) . its level was similar in ra patients in remission or not induced by anti - tnf therapy . however , normal mmp-3 level in ra patients treated with tocilizumab was predictive to absence of relapse after tocilizumab cessation . to summarize , high mmp-3 level was associated with disease activity and joint progression in ra patients and should be used in association with usual inflammatory markers to follow therapy efficiency . however , this biomarker was never tested in patients in clinical remission to predict structural remission . another synovial biomarker considered in ra is the glycosylated form of pyridinoline ( pyd ) . pyd is mainly a bone resorption biomarker but is also related to remodeling of cartilage and synovium . the glycosylated analogue of pyd , glucosyl - galactosyl - pyd ( glc - gal - pyd ) , can be assessed in urine and appeared to be specific to synovial tissue . urinary glc - gal - pyd level was higher in patients with early ra than controls and its high level is associated with higher risk for the progression of joint damage . in established ra , urinary glc - gal - pyd was associated with changes of the erosion , joint space narrowing ( jsn ) , and the total sharp score . after one year of anti - tnf therapy , the levels of urinary glc - gal - pyd was similar in ra patients with or without progressive joint damage over one year of anti - tnf therapy , but its reduction over one year was higher in patients with progressive joint damage . these results suggested that , in some patients , other mechanisms were possibly involved than tnf related inflammation . the last synovium biomarker recently developed is the nitrated type iii collagen ( iiinys ) , which was explored in both osteoarthritis ( oa ) and ra patients . in patients with joint disorder , its level was the highest in ra patients which suggests that it is related to synovial tissue inflammation . we attempted to describe synovial biomarkers and put out their interest in ra management . despite many studies reviewed , no data are currently available to predict relapse in ra patients in remission then , we focused on three main cartilage biomarkers with a summary of their characteristics in table 2 . two are biomarkers of cartilage breakdown , whereas the third one is a biomarker of cartilage formation . cartilage is mainly composed of collagen type ii ( 70% ) and proteoglycans including aggrecan which is the most abundant one . mmps and aggrecanases are mediators of cartilage degradation . collagen type ii c - telopeptide ( ctx - ii ) is a neoepitope generated from mmps , derived from the carboxy - terminal part of type ii collagen . in early ra , urinary ctx - ii level was higher than in controls , and patients with high ctx - ii level have a higher risk for the progression of joint damage over 1 year , independent of the extent of joint destruction at baseline and of clinical indices of disease activity . in established ra , urinary ctx - ii level was associated with rapid radiologic progression   or changes of the jsn sharp score over one year . then , ctx - ii was assessed during anti - tnf therapy in ra patients . after one year of anti - tnf therapy , the levels of urinary ctx - ii were similar in ra patients with or without progressive joint damage over one year of anti - tnf therapy . in patients with progressive joint damage , reduction of urinary ctx - ii was higher than in others . cartilage oligomeric matrix protein ( comp ) is a noncollagenous extracellular matrix protein mainly found in cartilage maintaining the integrity of the collagen network . serum comp was reduced in ra patients in remission induced by anti - tnf therapy compared to other patients . in early ra , early changes in serum comp levels were related to radiological outcome over the first 5 years . serum propeptide of type iia procollagen ( piianp ) arises from the maturation of type iia procollagen . its level was decreased in patients with oa or ra . in ra patients treated with low - dose corticosteroids , no data are at this time available to describe their interest to predict relapse in ra patient in remission . bone homeostasis is highly regulated by balance between new bone formation and removing old bone . bone formation markers included the serum bone formation markers total osteocalcin ( oc ) , the alkaline phosphatase bone isoenzyme ( balp ) , and the c- and n - propeptide of type i collagen ( picp and pinp ) . bone degradation is driven by osteoclasts and results in stimulation by rankl induced by il-1 , il-6 , or tnf . osteoclasts secrete cathepsin k , which degrades the collagen type i and releases c - terminal crosslinked telopeptide of type i collagen ( ctx - i ) , or n - terminal crosslinked telopeptide of type i collagen ( ntx ) neoepitope . the crosslinked carboxyterminal telopeptide of type i collagen ( ictp ) is another fragment of c - telopeptide end , which is not released with cathepsin k action but probably mmps [ 52 , 53 ] . other type i collagen crosslinks are pyridinoline ( pyd ) and deoxypyridinoline ( dpd ) . in established ra , uncoupling with low level of bone formation markers and high bone resorption markers was described in 1999 . oc , a bone formation marker , was reduced in ra without destruction compared to controls . on the contrary , ctx - i , a catabolic bone marker , is higher in ra patients with destruction compared to other ra patients . this uncoupling was recently confirmed by using an innovative way to assess bone damage in ra by high - resolution peripheral quantitative computed tomography ( hr - pqct ) . trap 5b level , a catabolic bone marker , was associated with bone erosions , whereas bone alkaline phosphatase ( bap ) was associated with osteophytes . furthermore , in longitudinal studies , catabolic bone markers ( ctx - i or pyd ) are also good predictors for radiologic progression in ra [ 47 , 58 , 59 ] . like cartilage and synovium turnover markers , ratio between bone formation markers and bone resorption markers increased during one year of treatment , suggesting improvement of the bone remodeling balance , mainly due to a decrease in bone resorption . a differential effect was observed at one year of anti - tnf therapy between ictp and ctx - i . ictp , which is related to mmps activity , remained decreased at one year , whereas ctx - i level , which is related to cathepsin k , returned to its baseline level at one year . this suggests a strong effect of anti - tnf on local subchondral bone related to joint inflammation . since tnf blockers already showed a reduction of the bone biomarker unbalance , tnf blockers also demonstrated a positive effect on bone mineral density in ra patients with or without a clinical response as observed at the joint level . all these data support that anti - tnf therapy is not only able to prevent joint destruction , but it is also able to prevent bone loss in ra patients . similarly , with tocilizumab , bone formation biomarker pinp increased whereas bone resorption markers , ictp and ctx - i , decreased . this suggests a nonspecific effect of a pathway but an effect on suppression of joint inflammation . denosumab reduced both serum pinp and ctx - i levels over one year , whereas urinary ctx - ii decreased only at 3 months . since denosumab targets rankl , but not a proinflammatory cytokine , ra disease was not improved , but it reduced erosion progression . so according to the target , drugs have different effects . blocking inflammation reduces bone loss , but blocking pathway induced in bone loss reduced it without effect on ra activity . among all these biomarkers , only ctx - i has demonstrated its ability to be associated with joint destruction , sensitivity to treatment , and prediction of joint progression we showed that synovium , cartilage , and bone turnover biomarkers are correlated with ra activity . to summarize furthermore , these biomarkers could be useful to identify ra patients with high risk of rapid disease progression . since these biomarkers reflected different compartments involved in ra , they will be useful to define structural remission in ra . some of these reviewed biomarkers compose the multibiomarker disease activity ( mbda ) test developed to quantify ra disease activity . recent data suggested that low mbda was associated with clinical remission criteria [ 67 , 68 ] . treat - to - target strategy emerged since few years to manage early ra patients . only one study combining clinical and biomarkers demonstrated its utility in the treat - to- target strategy . however , we need more studies to generate more data to define the place of these biomarkers in ra remission . at this time