Anabolic indices of matrix proteins identify regenerative small RNA intrinsic to human cartilage.

Some vertebrates regenerate appendages through the action of small noncoding RNAs (smRNAs) expressed in their blastema. Inspired by these models, we investigated whether similar smRNA-mediated mechanisms might contribute to the intrinsic repair capacity of human cartilage. Although humans lack the capacity to regenerate entire limbs, digit tip regrowth and joint cartilage repair following joint distraction suggest latent regenerative potential.

Biomarkers of aging as it relates osteoarthritis: we can't improve what we can't measure.

Aging is the largest risk factor for the development of osteoarthritis (OA), a major contributor to increased years lived with disability. This review reflects on how age-related changes relevant to OA have been measured at various length scales. Key discoveries include increased chondrocyte DNA damage with age and the disruption of matrix homeostasis by cellular senescence.

Molecular biomarker approaches to prevention of post-traumatic osteoarthritis.

Up to 50% of individuals develop post-traumatic osteoarthritis (PTOA) within 10 years following knee-joint injuries such as anterior cruciate ligament rupture or acute meniscal tear. Lower-extremity PTOA prevalence is estimated to account for ≥12% of all symptomatic osteoarthritis (OA), or approximately 5.6 million cases in the USA.

Serum proteomic panel validated for prediction of knee osteoarthritis progression.

Objective: To further validate a serum proteomics panel for predicting radiographic (structural) knee OA progression.

Design: Serum peptides were targeted by multiple-reaction-monitoring mass spectrometry in the New York University cohort (n ​= ​104). Knee OA progression was defined as joint space narrowing ≥1 in the tibiofemoral compartment of one knee per study participant over a 24-month follow-up.

Association of Dipeptidylpeptidase 4 (CD26) With Chondrocyte Senescence and Radiographic Progression in Knee Osteoarthritis.

Objective: To evaluate the association of dipeptidylpeptidase 4 (DPP-4; also known as CD26) with cellular senescence of human cartilage and progression of knee osteoarthritis (OA).

Methods: Articular cartilage sections and chondrocytes were acquired from 35 individuals undergoing total knee replacement for OA to evaluate the following: 1) the association between OA severity and established senescence markers (senescence-associated β-galactosidase activity and p16), which was quantified using immunohistochemistry and flow cytometry (n = 19 samples); 2) the coexpression of DPP-4 with established senescence markers, which was assessed using flow cytometry; and 3) expression levels of anabolic and catabolic genes, senescence-related genes, and senescence-associated secretory phenotypes in DPP-4+ and DPP-4- cells, which were isolated using fluorescence-activated cell sorting or magnetic-activated cell sorting (n = 16 samples). The concentration of soluble DPP-4 was measured in samples of synovial fluid and samples of plasma from the Prediction of Osteoarthritis Progression cohort and then evaluated for association with the severity of radiographic knee OA at baseline (n = 65 samples) and the progression of structural radiographic OA (n = 57 samples) over a 3-year period.

CBX4 Regulates Replicative Senescence of WI-38 Fibroblasts.

Cellular senescence is characterized by cell cycle arrest and senescence-associated secretory phenotypes. Cellular senescence can be caused by various stress stimuli such as DNA damage, oxidative stress, and telomere attrition and is related to several chronic diseases, including atherosclerosis, Alzheimer's disease, and osteoarthritis. Chromobox homolog 4 (CBX4) has been shown to alleviate cellular senescence in human mesenchymal stem cells and is considered a possible target for senomorphic treatment.

TNF-α Carried by Plasma Extracellular Vesicles Predicts Knee Osteoarthritis Progression.

Objectives: To identify plasma extracellular vesicles (EVs) associated with radiographic knee osteoarthritis (OA) progression.

Methods: EVs of small (SEV), medium (MEV) and large (LEV) sizes from plasma of OA participants (n=30) and healthy controls (HCs, n=22) were profiled for surface markers and cytokine cargo by high-resolution flow cytometry. The concentrations of cytokines within (endo-) and outside (exo-) EVs were quantified by multiplex ELISA.

Synergistic Roles of Macrophages and Neutrophils in Osteoarthritis Progression.

Objective: To evaluate the role of immune cells and their effector cytokines in the pathogenesis and progression of knee osteoarthritis (OA) in matched OA synovial fluid (SF) and synovial tissue samples.

Methods: Cells from matched samples of synovial tissue and SF acquired from individuals undergoing total knee replacement for OA (n = 39) were characterized for immune cell-associated surface markers and intracellular cytokine expression using polychromatic flow cytometry. Additional individuals with radiographic knee OA (Kellgren/Lawrence severity grades ≥1) who had available etarfolatide (inflammatory cell) imaging (n = 26) or baseline and 3-year data on progression of radiographic knee OA (n = 85) were also assessed.

Analysis of "old" proteins unmasks dynamic gradient of cartilage turnover in human limbs.

Unlike highly regenerative animals, such as axolotls, humans are believed to be unable to counteract cumulative damage, such as repetitive joint use and injury that lead to the breakdown of cartilage and the development of osteoarthritis. Turnover of insoluble collagen has been suggested to be very limited in human adult cartilage. The goal of this study was to explore protein turnover in articular cartilage from human lower limb joints.

Synovial fluid biomarkers associated with osteoarthritis severity reflect macrophage and neutrophil related inflammation.

Background: To identify a synovial fluid (SF) biomarker profile characteristic of individuals with an inflammatory osteoarthritis (OA) endotype.

Methods: A total of 48 knees (of 25 participants) were characterized for an extensive array of SF biomarkers quantified by Rules Based Medicine using the high-sensitivity multiplex immunoassay, Myriad Human InflammationMAP® 1.0, which included 47 different cytokines, chemokines, and growth factors related to inflammation.

Cartilage biomarkers in the osteoarthropathy of alkaptonuria reveal low turnover and accelerated ageing.

Objective: Alkaptonuria (AKU) is a rare autosomal recessive disease resulting from a single enzyme deficiency in tyrosine metabolism. As a result, homogentisic acid cannot be metabolized, causing systemic increases. Over time, homogentisic acid polymerizes and deposits in collagenous tissues, leading to ochronosis.

Elucidating the Molecular Composition of Cartilage by Proteomics.

Articular cartilage consists of chondrocytes and two major components, a collagen-rich framework and highly abundant proteoglycans. Most prior studies defining the zonal distribution of cartilage have extracted proteins with guanidine-HCl. However, an unextracted collagen-rich residual is left after extraction.

Xanthine oxidase injurious response in acute joint injury.

Background: While acute trauma is a major cause of osteoarthritis, its etiology is poorly understood. We sought to determine whether xanthine oxidase (XO), a major producer of reactive oxygen species, plays a role in the early events of acute joint injury.

Methods: We analyzed synovial fluid from 23 subjects with recent severe acute knee injury.

Biomarkers and proteomic analysis of osteoarthritis.

Our friend and colleague, Dr. Dick Heinegård, contributed greatly to the understanding of joint tissue biochemistry, the discovery and validation of arthritis-related biomarkers and the establishment of methodology for proteomic studies in osteoarthritis (OA). To date, discovery of OA-related biomarkers has focused on cartilage, synovial fluid and serum.