Summary
A study of human and great-ape cartilage found roughly threefold lower glycosaminoglycan levels in humans and traced this difference to widespread changes in skeletal gene regulation. The authors suggest the shift may have influenced human skeletal traits and vulnerability to degenerative disease.
A study published in Nature on 23 September 2026 links human-specific changes in skeletal gene regulation to substantially lower levels of glycosaminoglycans in human cartilage than in other great apes. Across 139 cartilage samples from 42 people and seven great-ape individuals, the researchers measured roughly threefold lower levels in humans overall, with reductions of 2.6- to fourfold across each of the eight joint types examined.
Glycosaminoglycans (GAGs) are sugar chains attached to proteins in the cartilage extracellular matrix. They help form the hydrated tissue around cartilage cells and contribute to cartilage’s mechanical properties. The researchers’ results point to an evolutionary shift in how this matrix is regulated and built.
How the researchers traced regulatory changes
The team tested 561,410 human-derived DNA substitutions in candidate promoters and enhancers—regulatory regions that can influence when and how strongly genes are expressed. Using massively parallel reporter assays in human fetal chondrocytes, cartilage cells, they measured how human and great-ape versions of these sequences affected expression. The assay identified 15,077 candidate regulatory elements with significant human-specific activity differences.
To examine gene regulation beyond the tested substitutions, the researchers also studied human–chimpanzee and human–gorilla hybrid osteochondral progenitor cells. In these cells, the two species’ genomes share a nucleus and regulatory environment, helping the team identify expression differences associated with changes acting on the DNA itself. The analysis found 4,463 human-specific changes in cis-regulatory expression.
Across these datasets, GAG biosynthesis emerged as a prominent area of change. In the hybrid-cell analysis, 17 of 21 significantly differentially expressed human GAG-related genes were downregulated. One example was CSGALNACT1, which helps initiate chondroitin-sulfate chain elongation: its human allele was expressed 42% less than the chimpanzee allele and 34% less than the gorilla allele in the reported comparisons.
The study also found an evolutionary change in ACAN, the gene for aggrecan, a major cartilage protein that carries GAG chains. Human sequences averaged six additional repeats in a region encoding GAG attachment sites—12 additional sites—compared with non-human great apes. This increase sits alongside the evidence for reduced GAG production, so the net effect on cartilage could not be inferred from gene regulation alone. The researchers therefore also measured GAG levels directly in joint tissue.
What the cartilage difference could mean
The tissue measurements showed that the regulatory changes correspond to a pronounced difference in cartilage composition. Sulfated GAG levels were measured with a dimethylmethylene blue assay and normalized to DNA content. The human reduction appeared across all eight joint types, and the researchers reported that age and sex did not explain the difference.
The authors suggest that lower GAG levels may have contributed to human skeletal traits and increased susceptibility to degenerative skeletal diseases, including osteoarthritis. Their interpretation draws on the regulatory results, the cross-species tissue comparison and known links between GAG biology and skeletal conditions. The study did not test whether the evolutionary difference directly causes disease in people, or whether changing GAG levels would alter disease outcomes.
The findings establish a broad pattern of human skeletal evolution involving both gene regulation and cartilage composition. The authors report signatures of lineage-specific selection, while noting that the evolutionary changes could reflect adaptation, relaxed constraints on GAG production, or a combination of forces.