Spatial lipid atlas of human articular cartilage: bridging cartilage physiology, pathology, and engineering

Lipids are a class of essential biomolecules. Numerous studies have uncovered the role of lipids in tissue homeostasis and disease progression, demonstrating the close correlation between the lipid distribution and tissue functionality. In human articular cartilage, lipid constitutes less than 1% of its dry weight in human articular cartilage, but they are deeply associated with the health of cartilage microenvironment. However, information about the lipid composition and spatial distribution within human articular cartilage remains limited. Consequently, their roles in modulating chondrocyte behaviors are still elusive. Therefore, it is necessary to establish a high-resolution spatial map of lipids within full-depth articular cartilage. Spatial lipidomics revealed a distinct bilayer lipid metabolic pattern, which corresponded to different chondrocyte phenotypes in the respective layers. Specifically, the epi-cartilage was characterized by an abundance of membrane-related amphipathic phospholipids, and chondrocytes in this layer exhibited functional enrichments in lipid transport and extracellular matrix (ECM) secretion. In contrast, the endo-cartilage showed a significant increase in lysophospholipids, aligning with a pro-mineralization transcriptomic signature. Furthermore, the ceramide (CER) mediated compensatory ECM secretion was observed in early OA, which is achieved by the increased membrane trafficking. The therapeutic potential of CER-targeted OA intervention was examined and found to promote ECM production and cellular viability. However, adverse outcomes were identified with long-term exposure, probably attributed to excessive CER accumulation within the cartilage ECM. In summary, this study established a spatiotemporal lipid landscape of human articular cartilage in both normal and early OA conditions. The identification of a bi-layer lipid metabolic model, along with the disease-specific self-regulation of chondrocyte secretion mediated by CER metabolism, represents a significant advancement in our understanding of cartilage tissue physiology and pathology. Moreover, this study facilitates the development of potential cartilage engineering strategies. The attempts to translate analytical findings into an OA treatment not only validated the lipid bilayer model, but also affirmed the potential for developing biomimetic cartilage engineering strategies based on the spatial lipidomic map.