Why human joint cartilage has fewer water-binding molecules

Human joint cartilage is chemically different from that of our closest living relatives. A study published in Nature found that it contains, on average, roughly one-third as much of a group of carbohydrate chains that help cartilage retain water and withstand pressure. The difference appears to be associated with evolutionary changes in gene regulation, raising a provocative possibility: some of the changes that accompanied the evolution of the human skeleton may also have left our joints more vulnerable.

These molecules are called glycosaminoglycans, or GAGs. They are long sugar chains attached to proteins such as aggrecan, forming part of the extracellular matrix surrounding cartilage cells. Their negative electrical charges attract water.

Together with the collagen framework, this highly hydrated material allows cartilage to deform under pressure and recover when the load is removed. It is an important part of what makes joint surfaces resilient.

A threefold difference across eight joints

The researchers examined 139 cartilage samples from 42 humans and seven individual non-human great apes, representing eight types of joints. They measured sulfated GAGs and normalized the readings to the amount of DNA in each sample.

GAG levels were relatively similar among the non-human apes. Human samples, by contrast, contained about three times less overall. The difference appeared in every joint type studied, ranging from 2.6-fold to fourfold.

That pattern makes a simple explanation based solely on the physical stresses of bipedal walking less convincing. The lower levels were found not only in joints that bear greater loads in humans, but also in joints exposed to comparable or lower loads than those of other apes.

Differences in age and sex did not account for the finding either.

There is an important boundary to that result. Only seven non-human apes were represented in the tissue comparison, and the measurements describe cartilage composition, not how much force a particular joint can tolerate or the likelihood that its owner will develop osteoarthritis.

The genetic switches behind the cartilage

To investigate where the difference might come from, the team examined the DNA sequences that control when genes are expressed.

They tested 561,410 changes that arose along the human lineage in candidate regulatory regions. In an assay using cartilage cells, 15,077 regulatory elements showed human-specific activity.

The investigators then used an unusual laboratory system: cells created by fusing cultured human cells with those of chimpanzees or gorillas, and directing them toward bone-and-cartilage precursor states.

These were hybrid cells, not hybrid animals. Because DNA from both species operated in a shared cellular environment, the researchers could compare gene regulation while reducing many of the confounding differences between species.

One of the clearest patterns involved genes needed to make GAGs. Many showed lower activity on the human side. The gene CSGALNACT1, which contributes to the extension of chondroitin sulfate chains, offered a particularly strong example of regulatory changes associated with reduced expression.

Yet the evolutionary changes did not all point the same way.

The human version of ACAN, the gene encoding aggrecan, gained extra repeats that provide potential attachment sites for GAG chains. Despite having more such sites, human cartilage ultimately contained substantially less GAG.

That contrast suggests a remodeling of several interacting components rather than one straightforward genetic switch.

An evolutionary trade-off, or a clue?

The findings may help explain an enduring puzzle. Osteoarthritis and other degenerative skeletal disorders are much more common in humans than in other great apes.

Because GAGs contribute to the mechanical properties and maintenance of cartilage, the authors propose that a reduced baseline amount might be one factor in that vulnerability.

The study does not establish that explanation as a cause. It did not follow people over time to measure their risk of osteoarthritis, demonstrate that the identified regulatory changes cause the disease, or show that walking upright directly produced the GAG reduction.

Nor does a threefold difference in GAG abundance mean a threefold difference in cartilage strength or disease risk.

What the researchers have established is a striking difference at a level that bones alone cannot reveal.

Human skeletal evolution involved changes not only in the shape of the pelvis, spine and limbs, but also in the molecular material coating joint surfaces.

Some of our distinctive evolutionary history may be written into the cartilage between those bones.