A multidisciplinary team led by Duke researchers has identified a previously unknown biological pathway that plays a critical role in cartilage integrity and bone strength—findings that may inform future research into osteoarthritis, skeletal development, and bone density disorders.
The study, recently published in Nature Chemical Biology, was co‑led by Jen‑Tsan Ashley Chi, MD, PhD, Professor in Molecular Genetics and Microbiology; Pei Zhou, PhD, James B. Duke Distinguished Professor of Biochemistry; and Matthew J. Hilton, PhD, Professor in Orthopaedic Surgery and Cell Biology. The work reflects extensive collaboration across Duke departments and with investigators at other institutions.
At the center of the discovery is MESH1, a protein newly identified as a key regulator of sulfation—an essential process that helps determine how cartilage and bone are built and maintained. Sulfation influences the structure and function of glycosaminoglycans, molecules that allow cartilage to retain water, absorb shock, and withstand repetitive joint loading.
“Cartilage and bone are highly dependent on properly sulfated extracellular matrix,” said Hilton. “By identifying how sulfation is regulated inside cells, we now have a better understanding of one of the fundamental mechanisms that supports joint durability and skeletal strength.”
While scientists have long understood how cells produce PAPS, the universal sulfate donor, it was unclear how its availability is controlled. The Duke‑led team discovered that MESH1 acts as a molecular brake, limiting sulfation by breaking down excess PAPS inside cells. This regulatory step appears to be especially important in tissues like cartilage, where matrix composition directly affects biomechanical performance.
Using a combination of biochemical analysis, structural studies, and cellular models, the researchers showed that MESH1 operates within the Golgi apparatus—the cellular hub where sulfated matrix molecules are assembled. When MESH1 activity was reduced in cartilage‑forming cells, sulfation increased, leading to higher production of sulfated glycosaminoglycans.
The findings were further validated in animal models. In mice lacking the Mesh1 gene, researchers observed elevated sulfation of the matrix in joint cartilage and improved bone density, suggesting that this pathway influences both cartilage quality and skeletal integrity.
“Seeing coordinated effects in cartilage and bone underscores how interconnected these tissues are,” Hilton said. “This is particularly relevant for orthopaedics, where joint degeneration and bone loss often coexist.”
The study also demonstrated that MESH1’s role is conserved across species, reinforcing its importance as a core biological mechanism rather than a species‑specific effect.
The project highlights the power of team science. Structural biology, molecular genetics, and musculoskeletal biology were all essential to defining MESH1’s function and its downstream effects.
“This work would not have been possible without close collaboration across disciplines,” said Zhou. “By combining structural insights with functional models, we were able to connect molecular regulation directly to tissue‑level outcomes.”
Although the research is not yet clinical, its implications are significant for orthopaedic science. Abnormal matrix sulfation is associated with osteoarthritis, skeletal dysplasias, impaired growth plate function, and reduced bone strength. Understanding the pathways that regulate matrix composition may eventually help researchers identify new strategies to preserve cartilage health or enhance skeletal resilience.
“This discovery gives the field a new lens through which to study cartilage degeneration and bone disorders,” Hilton said. “It adds an important piece to the puzzle of how musculoskeletal tissues maintain their structure over time.”
The study, “MESH1 functions as a metazoan PAPS phosphatase to regulate sulfation,” is available online in Nature Chemical Biology.