Molecular Classification of Knee Osteoarthritis

Abstract

Knee osteoarthritis (KOA) is the most common form of joint degeneration with increasing prevalence and incidence in recent decades. KOA is a molecular disorder characterized by the interplay of numerous molecules, a considerable number of which can be detected in body fluids, including synovial fluid, urine, and blood. However, the current diagnosis and treatment of KOA mainly rely on clinical and imaging manifestations, neglecting its molecular pathophysiology. The mismatch between participants’ molecular characteristics and drug therapeutic mechanisms might explain the failure of some disease-modifying drugs in clinical trials. Hence, according to the temporal alteration of representative molecules, we propose a novel molecular classification of KOA divided into pre-KOA, early KOA, progressive KOA, and end-stage KOA. Then, progressive KOA is furtherly divided into four subtypes as cartilage degradation-driven, bone remodeling-driven, inflammation-driven, and pain-driven subtype, based on the major pathophysiology in patient clusters. Multiple clinical findings of representatively investigated molecules in recent years will be reviewed and categorized. This molecular classification allows for the prediction of high-risk KOA individuals, the diagnosis of early KOA patients, the assessment of therapeutic efficacy, and in particular, the selection of homogenous patients who may benefit most from the appropriate therapeutic agents.

Osteoarthritis as an Umbrella Term for Different Subsets of Humans Undergoing Joint Degeneration: The Need to Address the Differences to Develop Effective Conservative Treatments and Prevention Strategies

“…The knee OA patient population is heterogeneous, with different subsets having different characteristics or phenotypes. This heterogeneity can be defined using several different approaches [ 16 , 17 , 18 , 19 ], including the categories discussed in this review. The more successful the research community becomes in delineating subtypes of OA, the more understanding will emerge to rationalize the development of effective interventions.…”

“…This concept that OA is heterogeneous [ 14 , 15 ] and that sub-typing or phenotyping of OA is needed has also been raised by others [ 16 , 17 , 18 , 19 , 20 ] using a variety of criteria. Thus, some are related to metabolic phenotype [ 16 , 18 , 20 ], while others rely on patient characteristics at other levels [ 17 , 19 ]. In addition, biomarkers may be of use to identify subsets of patients with unilateral knee OA who may progress to bilateral knee OA [ 21 ].…”

An osteoarthritis subtype characterized by synovial lipid metabolism disorder and fibroblast-like synoviocyte dysfunction

“…In particular, molecular markers are directly related to the pathological mechanism of OA. Molecular markers can sensitively reflect the characteristics of different microenvironment changes and metabolic disorders and are often used for the early diagnosis and subtype identification of OA [ 16 ]. For example, several studies identified OA subtypes characterized by higher levels of inflammatory markers [ 17 , 18 ].…”

“…Lv Z. et al. reviewed the characteristics of molecular markers in different stages of knee OA from before OA to late-stage OA and proposed four subtypes of progressive OA [ 16 ]. These strategies are helpful for patients with different OA subtypes to choose the most effective disease-modifying drugs according to their pathological characteristics.…”

Does Bisphosphonate Increase the Sclerosis of Tibial Subchondral Bone in the Progression of Knee Osteoarthritis—A Propensity Score Matching Cohort Study Based on Osteoarthritis Initiative

“…Vaysbrot's meta-analysis ( 37 ) proposed that bisphosphonate might be beneficial in certain subsets of patients who display high rates of subchondral bone turnover. Lv et al ( 38 ) proposed that progressive KOA could be divided into four subtypes based on pathophysiology: cartilage degradation-driven, bone remodeling-driven, inflammation-driven, and pain-driven subtypes. Theoretically, bisphosphonate is most beneficial to the bone remodeling-driven KOA subtype.…”