All bones start off as cartilage. Cartilage generates an abundant and specialized matrix surrounding its cells (extracellular matrix) that promotes the growth of skeletal structures and is pivotal in maintaining a mobile lifestyle.

Osteoporosis, arthrosis, and other musculoskeletal diseases are the leading cause of chronic pain and loss of mobility worldwide. Changes in the extracellular matrix can lead to such chronic diseases in early childhood or at an advanced age.

To maintain proper organization of cartilage, processes that regulate bioenergy metabolism and the function of the extracellular matrix must synchronize. But crosstalk between these vital processes remains unclear.

Scientists in Germany have now adopted a combined approach of high-resolution single-cell RNA sequencing (scRNA-Seq), mass spectrometric matrisome analysis, and atomic force microscopy to understand the exchange between the matrix outside cells and the mitochondrial respiratory chain inside cells, in mature cartilage.

The findings that may lead to the development of new diagnostic and therapeutic approaches for musculoskeletal diseases are published in an article in the Journal of Biological Chemistry, titled, “Mitochondrial respiratory chain function promotes extracellular matrix integrity in cartilage.”

Bent Brachvogel, PhD, head of experimental neonatology at the Faculty of Medicine and University Hospital Cologne, Germany, is a spokesperson of the research group, FOR2722 “New molecular factors of musculoskeletal extracellular matrix homeostasis” funded by the German Research Foundation (DFG), and the senior author of the study said, “The energy metabolism of the cell is very important for the production of the extracellular matrix, but the interactions between these components have not been sufficiently understood so far. We have demonstrated for the first time the importance of the mitochondrial respiratory chain as an essential energy supplier for extracellular matrix homeostasis in cartilage.”

Kristina Bubb, PhD, first author of the study added, “Our research has identified the mitochondrial respiratory chain as a new therapeutic target for treating a defective extracellular matrix in degenerative cartilage disease.”

As a model system, the scientists used mutant mice with selective genetic inactivation of the mitochondrial respiratory chain in cartilage tissue. The researchers reported that in one-month-old mutant mice a central area of the articular cartilage at the head of the femur bone in the upper thigh expanded abnormally showing disorganized cartilage cells (chondrocytes) and excessive extracellular matrix.

Through the scRNA-Seq analysis, the researchers also uncovered reduced mitochondrial respiratory chain genes in a group of chondrocytes and a unique regulation of genes that synthesized the extracellular matrix in cartilage cells that do not face the hip joint (non-articular chondrocytes).

These changes in gene expression are linked to changes in the composition, structure, and stiffness of the extracellular matrix in mature cartilage tissue, particularly a change in the amount of collagen in the cartilage tissue and the degree to which the elastic collagen fibers are crosslinked to form a stable mesh.

The team showed that loss of mitochondrial respiration led to disorganization, expansion, and stiffening of the cartilage matrix due to impaired metabolic signaling and consequent changes in the composition and mechanical properties of the cartilage.

“These results demonstrated that mitochondrial respiratory chain dysfunction is a key factor that can promote extracellular matrix integrity and mechanostability in cartilage and presumably also in many other tissues,” the authors concluded.