CASC20 IS A SUSCEPTIBILITY GENE FOR HETEROTOPIC OSSIFICATION AFTER HIP ARTHROPLASTY

Journal and index pages often block iframe embedding. This reader keeps the evidence details in Orthonotes and leaves the source page one click away.

Abstract

Purpose The term heterotopic ossification (HO) describes bone formation that occurs within tissues that do not normally ossify, resulting in pain and disability. However, why some patients suffer HO and others do not is unstudied. Methods Here, we use genome-wide association analysis in a population of ~1,000 patients after hip replacement (~40% with some degree of HO formation) to identify risk genes for the disease. We then show in experimental models how the identified risk genes exert their biological effects. Results In the genome-wide study we identify the long non-coding RNA-encoding gene CASC20 as a susceptibility locus for HO, replicating this finding in an independent study population (P=2.71x10-11). We show CASC20 is expressed in bone and is upregulated upon BMP2 induction in stem cells, followed by RUNX2 and OSTERIX upregulation and bone formation. We subsequently show that CASC20 over-expression in human mesenchymal stem cells, both adipose-derived and bone marrow-derived, accelerates their differentiation into bone through direct osteogenesis, whilst down-regulating cartilage formation, indicating that CASC20 acts as a molecular switch from chondrogenesis to turn on bone formation. Conclusion These findings provide the first insights that demonstrate a genetic component to post-traumatic HO, identifying CASC20 as a novel promoter of bone formation.