Evolutionary Selection and Constraint on Human Knee Chondrocyte Regulation Impacts Osteoarthritis Risk

Abstract

During human evolution, the knee adapted to the biomechanical demands of bipedalism by altering chondrocyte developmental programs. This adaptive process was likely not without deleterious consequences to health. Today, osteoarthritis occurs in 250 million people, with risk variants enriched in non-coding sequences near chondrocyte genes, loci that likely became optimized during knee evolution. We explore this relationship by epigenetically profiling joint chondrocytes, revealing ancient selection and recent constraint and drift on knee regulatory elements, which also overlap osteoarthritis variants that contribute to disease heritability by tending to modify constrained functional sequence. We propose a model whereby genetic violations to regulatory constraint, tolerated during knee development, lead to adult pathology. In support, we discover a causal enhancer variant (rs6060369) present in billions of people at a risk locus (GDF5-UQCC1), showing how it impacts mouse knee-shape and osteoarthritis. Overall, our methods link an evolutionarily novel aspect of human anatomy to its pathogenesis.

Association between growth differentiation factor 5 rs143383 genetic polymorphism and the risk of knee osteoarthritis among Caucasian but not Asian: a meta-analysis

“…Secondly, Huang et al's meta-analysis explores the association between all kinds of osteoarthritis and GDF5 rs143383 polymorphisms, which cannot precisely describe the relationship between GDF5 rs143383 polymorphisms and the susceptibility of knee osteoarthritis [12]. Although genetic variants can have different effect sizes in different populations, as is shown for GDF5 for African populations vs Eurasian populations [43][44][45], it is highly unlikely that this is the case, based on the data presented by the authors. These studies focused on apes, so there is still a gap between apes and humans.…”

Positive Feedback Regulation Between USP15 and ERK2 Promotes Cartilage Repair in Experimental Osteoarthritis

“…OA is the most common type of arthritis with in ammatory disease in the synovial joints (32,33) . It is characterized by gradual degeneration of articular cartilage and changes in the structure and function of the entire joint (34,35) . In recent years, it has been reported that the canonical SMAD signaling of the TGF-β signaling pathway contribute signi cantly to cartilage maintenance and repair.…”

Association between Growth Differentiation Factor 5 rs143383 Genetic Polymorphism and the Risk of Knee Osteoarthritis among Caucasian But Not Asian: A Meta-analysis

“…Secondly, Xin Huang's meta-analysis explores the association between all kinds of osteoarthritis and GDF 5 rs143383 polymorphisms, which can't precisely describe the relationship between GDF 5 rs143383 polymorphisms and the susceptibility of knee osteoarthritis [12]. Although genetic variants can have different effect sizes in different populations, as is shown for GDF5 for African populations vs Eurasian populations [43][44][45], it is highly unlikely that this is the case, based on the data presented by the authors. These studies focused on apes, so there is still a gap between apes and humans.…”