Textbooks have said for decades that haemoglobin is found in the red blood cells (RBCs), that it makes blood red, carries oxygen, and is essential for our survival.

A new and serendipitous discovery has revealed that haemoglobin isn’t used by RBCs alone. In a study published in Nature, scientists from China have reported that chondrocytes – cells that make cartilage, the connecting tissue between bones – also make haemoglobin and seem to depend on it for their survival.

‘Haemoglobin bodies’

Feng Zhang, a pathologist in the Fourth Military Medical University in China, had been working on bone development since 2010. In 2017, when he was studying growth plates – cartilaginous tissue at the end of certain long bones that allows the bones to become longer – he stumbled upon a few spherical blob-like structures. They seemed to bear an uncanny resemblance to RBCs, and they contained haemoglobin.

Dr. Zhang then teamed up with Quiang Sun at the Beijing Institute of Biotechnology and used advanced microscopy techniques to investigate further.

Picture what happens when oil is mixed into water: the oil separates out into little globules in a process called phase separation. That’s what seemed to be happening in the chondrocytes in the cartilage as well. Dr. Zhang ascertained that the chondrocytes within the growth plates of newborn mice were not only producing large amounts of haemoglobin, but also that it was coalescing and forming large blobs without a membrane.

The scientists called these blobs haemoglobin bodies, or Hedy.

The haemoglobin does something

Now that they knew chondrocytes were making haemoglobin bodies, the question was: were the Hedy functional? That is, did they actually do something? To test this, the scientists used genetically modified mice, in this case mice in which the gene making haemoglobin had been removed. These mice produced almost no haemoglobin molecules and they died as embryos. But it turned out that if one looked closely at the growth plate cartilage tissue from these mice, most of the chondrocytes were dying.

Removing the gene that made haemoglobin specifically in the cartilage tissue also resulted in the same outcome: cell death among the chondrocytes. It was clear that Hedy was essential for the chondrocytes to live.

In RBCs, haemoglobin carries oxygen and makes sure that different parts of the body receive the oxygen to function correctly. The scientists conducted a series of experiments to check whether haemoglobin also carries oxygen in chondrocytes. First, they checked if the cartilage cells showed signs of stress before dying when haemoglobin molecules were absent. They focused on a special type of stress called hypoxic stress, caused by low-oxygen conditions. And indeed they did: cartilage that didn’t contain haemoglobin showed signs of hypoxic stress.

An oxygen store

Now they knew that the absence of haemoglobin caused the chondrocytes to go through some sort of low-oxygen stress. They then wanted to see how normal and haemoglobin-free chondrocytes behaved when there is little oxygen in the cells’ environment. The researchers proceeded to test the cells in a low-oxygen, or hypoxic, environment. In the presence of haemoglobin, the cells seemed to release more oxygen. But in the absence of haemoglobin, the chondrocytes started dying.

This further confirmed their hunch that the haemoglobin in the chondrocytes was most likely storing oxygen and supplying it to the cells when required.

“What’s really interesting about this paper is that they picked up on this unusual finding and delved deep into its aspects,” said Noriaki Ono, a bone biologist at the University of Texas Health Science Center at Houston. He wasn’t involved in the study.

Haemoglobin in other places

In a developing growth plate, where oxygen is limited due to a lack of blood supply to the region, the chondrocytes still manage to thrive. Based on the scientists’ findings, it’s the haemoglobin molecules that manage to bring them the oxygen they need to survive.

“What surprised me the most was that cartilage tissue synthesised a large amount of hemoglobin to cope with hypoxic stress,” Dr. Zhang told this writer by email.

A 2003 study had shown that chondrocytes adapt to low oxygen by, among other things, using an alternate pathway to break down sugars to release energy – one that doesn’t require oxygen. This study shed light on a different mechanism with which chondrocytes dealt with reduced oxygen supply.

The scientists also found that cartilage in regions outside the growth plate, like the one in the ribs or the spine of mice, also contained haemoglobin. What we don’t know yet for sure is whether the haemoglobin in these regions plays a similar role, in storing and releasing oxygen.

‘Really exciting possibility’

“What is important in this paper is that it breaks down barriers between haematology and skeletal biology, and shows that, in fact, these fields are more connected than it seems,” said Gerard Karsenty, a professor studying skeletal biology at Columbia University, New York.

We also don’t know if the Hedy has more functions or other effects on cells in the growth plate. Dr. Ono, who discovered a bone-making stem cell population in the growth plate in 2018, is intrigued by the possibilities this discovery opens for stem cells and their fates in the growth plate. “One really exciting possibility is that the haemoglobin in the growth plate could be doing something about changing the … fate of stem cells in the growth plate,” he said.

The discovery of functional haemoglobin in cartilage also leads to the possibility that it plays a role in certain joint diseases. “There are many bone deformities that develop from defects in chondrocytes,” according to Dr. Ono. “Maybe there is more cell death in some conditions due to having something wrong with the chondrocyte haemoglobin.”

Dr. Zhang added that he “hopes this discovery can reinterpret the mechanisms underlying some joint diseases.”

Rohini Subrahmanyam is a freelance journalist.