Cartilage and bone as a peripheral phenotype in Spinal Muscular Atrophy (SMA) Acronym: SMACHONDRON

• Applicants: Privatdozent Dr. Kai Böker, Ph.D.; Professor Dr. Peter Claus; Privatdozent Dr. Christian Dullin; Professorin Dr. Anna-Kathrin Hell
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572490222

Spinal Muscular Atrophy (SMA) is a rare genetic disorder characterized by the loss of motor neurons, leading to muscle wasting and weakness. Although SMA is widely described as a disease with selective degeneration of motor neurons and a preferential neuromuscular phenotype, the SMN protein is ubiquitously expressed and increasing evidence suggests that in severe SMA, a multi-system phenotype occurs with several organ systems involved. This study investigates the pathophysiological changes in cartilage and the bone-cartilage interface associated with SMA by analyzing both patient-derived and mouse model samples. We employ a comprehensive set of methodologies to assess cellular and tissue-level changes, focusing on cell proliferation, differentiation, cartilage thickness, synchrotron analysis, and histological examination. Patient-derived samples and samples from affected mice (severe SMA “Taiwanese mouse model” and mild SMA 2B/- mice) will be analyzed to provide a comparative understanding of disease pathology. Cell proliferation and differentiation assays are conducted to evaluate the regenerative potential and cellular behavior in SMA-affected tissues. Histological analysis allows detailed visualization of the cartilage structure and assessment of any morphological abnormalities and extracellular matrix changes. µCT and synchrotron measurements provide a high-resolution, three-dimensional view of cartilage and the bone-cartilage interface, enabling precise measurement of cartilage thickness and volume. To further elucidate the molecular mechanisms we will perform collagen gene regulation analysis since we have found significant dysregulations of different collagens across peripheral organs. Since SMN is a major splicing assembly protein, we furthermore aim to analyze pre-mRNA splicing regulation in an unbiased way by long-read Oxford Nanopore transcriptome sequencing revealing splicing patterns and isoform expression. Clinical parameters like age, gender, walking ability, body mass index (BMI), number of SMN2 copies, vitamin D supplementation, laboratory parameters and the type and duration of treatment with SMA-specific therapy will be compared with mobility data and data on the range of motion by reviewing the SMArtCARE registry of these patients to further analyze the direct effect on the patient. In conclusion, this study provides a detailed characterization of cartilage pathology in SMA using a multifaceted approach. The combination of in vitro experiments, radiological imaging via µCT and synchrotron measurements, histological examination of patient and mice samples and the comparison with clinical parameters offer a comprehensive understanding of the structural and functional changes in cartilage associated with SMA. These findings not only enhance our knowledge of SMA pathology but also underscore the potential for targeting cartilage health in therapeutic strategies.

• DFG Programme: Research Grants
• International Connection: Italy, United Kingdom
• Co-Investigators: Professorin Dr. Frauke Alves; Professor Dr. Lars Knudsen
• Cooperation Partners: Dr. Giuliana Tromba; Professorin Haiyan Zhou, Ph.D.