A single protein called SERPINA3 appears to be essential for kickstarting cartilage formation, and researchers want to find out exactly how it works. Cartilage is the temporary scaffold for the developing skeleton, and later in life it cushions joints. The process that turns stem cells into cartilage—chondrogenesis—is poorly understood at the molecular level. The known master switch, SOX9, drives cartilage production, but what turns SOX9 on in the first place has remained a gap in knowledge. The team has shown that blocking SERPINA3 stops cartilage from forming properly in lab-grown tissue, and that SOX9 itself fails to appear. This suggests SERPINA3 acts earlier than any known regulator. This is fundamental science, not applied medicine. The immediate payoff will be a clearer picture of how skeletons are built. If the team identifies SERPINA3 as a novel regulator of SOX9, it would fill a significant gap in developmental biology. Down the line, a factor that promotes cartilage production could improve tissue engineering for joint repair—but that is years away. For now, the value lies in understanding a basic biological rule: how a simple protein inhibitor can orchestrate the first steps of building a skeleton.
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This project aims to determine the mechanism by which a key protein called SERPINA3 enables cartilage formation. During development, the vertebrate skeleton begins as cartilage, gradually becoming mineralised into bone. This cartilage is formed from stem cells, which condense and differentiate into cartilage cells – chondrocytes – laying down a mesh of proteins called the extracellular matrix (ECM). This process is known as chondrogenesis, the first stages in the formation of the skeleton. Chondrogenesis is driven by a master regulator, SOX9, which binds to DNA and drives the expression of genes required to make the cartilage ECM. Despite its importance, the regulation of early chondrogenesis, is not well understood. We have discovered that SERPINA3 – a serine proteinase inhibitor - is necessary for cartilage formation to occur. The SERPINA3 gene is switched on very early and robustly during chondrogenesis. When we block the production of SERPINA3, engineered cartilage is markedly reduced in size and is unable to effectively form ECM. Moreover, our global gene expression data demonstrate that SERPINA3 is essential for many genes switched on during chondrogenesis. When we blocked SERPINA3 expression, we observed loss of SOX9 protein induction at early time points during chondrogenesis. We hypothesise that: ‘SERPINA3 functions as an early mediator of chondrogenesis through direct or indirect regulation of SOX9, and has a non-redundant role in skeletal development’. Our hypothesis will be addressed by the following distinct yet complementary work packages/objectives (WP/Obj). WP1 (Objective 1): Define what the SERPINA3 protein interacts with, and how this changes during chondrogenesis. WP2 (Objective 2): Determine the mechanism by which SERPINA3 contributes to cartilage formation, using mutant proteins with altered function, and define the effect of SERPINA3 in signalling pathways essential in early chondrogenesis. WP3 (Objective 3): To define the role of SERPINA3 in chondrogenesis in the developing skeleton using Xenopus laevis (African clawed frog) as a model. The benefits of this proposal are wide-ranging. The immediate impact will be to significantly contribute to our understanding of the molecular events leading to cartilage formation. Identification of a novel regulator of SOX9 would be a significant development in this field. There may also be applications in the field of cartilage tissue engineering/regenerative medicine, with the establishment of a factor promoting cartilage production. This proposal complements BBSRC priorities in several areas. As we are examining the role of a novel player in early skeletal development, we are advancing ‘understanding of the rules of life’. Establishing how SERPINA3 contributes to skeletal development would ‘generate new knowledge about key biological principles’. The proposal harnesses the expertise of researchers with expertise in cartilage, protein biochemistry, gene editing, microscopy, Xenopus in vivo models, and as such harnesses ‘interdisciplinary and team science’. The BBSRC ‘recognis[es] the importance of knowledge exchange for research, skills, and careers development.’ As the Project Lead is an early-career researcher with a growing profile in the cartilage field, this award would significantly bolster his research capacity, grow his network and generate impactful outputs.
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