By: 26 March 2020
Age-related changes to the cartilaginous tissue of the spine could invite painful nerve growth

Researchers say they have added to evidence that the vast majority of low back pain in people may be rooted in an overgrowth of pain-sensing nerves into spinal cartilaginous tissue.

The new experiments were designed to investigate whether a painful overgrowth of sensory nerves into the cartilaginous endplates in the spine could be the root of these unexplained cases.

The findings at John Hopkins Medicine, published in Nature Communications, may eventually help develop new treatments that target abnormal nerve growth in the spine.

“The cartilage endplate is the cushion on a seat that makes it more comfortable. But, like similar tissue in knee and hip joints, it succumbs to wear and tear over time,” says Xu Cao, Lee Riley Professor of Orthopaedic Surgery and researcher in the Johns Hopkins Institute for Cell Engineering.

Cao and his team suspect that age-related changes in the tissues make up the spinal column provide fertile ground for abnormal nerve growth, making the load-bearing work of the spine painful.

The researchers analysed samples of the bony end plates of vertebrae from mice aged more than 20 months, the human equivalent of about 70-80 years old. The researchers found that the soft, cartilaginous tissue in the mice’s spines became hardened and resembled diffuse bone with a Swiss cheese-like structure.

In previous studies, Cao’s team found an ageing or instable spine induces the cartilage endplates to change into porous bony structures that provide spaces for nerves to penetrate the dense structure of the bone. A cell type, called osteoclasts, creates the porous bone structure where the cartilage should be. Cao thought that the signalling molecule netrin-1 secreted by osteoclasts during this process invited abnormal nerve growth and back pain.

“Cartilage does not typically have nerve and blood vessels. However, when cartilage becomes a porous bony structure with growth of nerve fibres, it could be the source of back pain,” says Cao.

Cao and his colleagues first analysed tissue samples from the spines of old mice under the microscope, labelling the hole-building osteoclasts and nerve fibres with fluorescent tags. They found that osteoclasts and nerve fibres were present in the same areas of vertebrae, suggesting that the osteoclasts could be signalling the nerve growth in some way, perhaps with netrin-1.

Next, the team designed an experiment to prevent the osteoclasts from producing the abnormal ‘Swiss-cheese’ bone growth and secreting netrin-1 to see if nerve growth in the cartilaginous tissue, and the accompanying pain, could be stopped.

They genetically engineered mice to lack the gene that codes for osteoclast formation, and performed a surgery on the mice to destabilise the joints between their vertebrae, mimicking similar instability seen in people with low back pain. The researchers found that the mice lacking osteoclast cells had fewer pain-sensing nerves in the endplates of their vertebrae than mice with the gene.

Cao says those results show that the porous structure of cartilaginous endplates is an important lead in understanding how unexplained low back pain develops. His team next plans to conduct laboratory experiments using compounds that slow the abnormal bone growth to test their potential to treat low back pain.

Source: John Hopkins Medicine
Reference: Shuangfei Ni, and others. Sensory innervation in porous endplates by Netrin-1 from osteoclasts mediates PGE2-induced spinal hypersensitivity in mice. Nature Communications, 2019; 10 (1) DOI: 10.1038/s41467-019-13476-9