Complete Loss of Cramp Promotes Experimental Osteoarthritis with Enhanced Chondrocyte Apoptosis in Mice

Osteoarthritis (OA) is the most prevalent form of joint arthritis, frequently associated with aging, mechanical wear, and inflammation. Our previous work demonstrated that cathelicidin-related antimicrobial peptide (Cramp) is upregulated in mouse OA cartilage, and that transient knockdown (KD) of Cramp in cultured chondrocytes decreases IL-1β-induced expression of matrix-degrading enzymes. The aim of this study was to determine the in vivo role of Cramp in OA pathogenesis using whole-body Cramp knockout (KO) mice. Normal skeletal development and growth plate morphology were assessed in E18.5d embryos and 2-week-old mice, respectively. Expression profiles of catabolic and anabolic genes were analyzed in primary chondrocytes derived from Cramp KO mice. OA in mouse knee joints was induced using intra-articular monosodium iodoacetate (MIA) injections or surgical destabilization of the medial meniscus (DMM). We observed that Cramp loss does not impact normal skeletal development. In contrast to our expectations, complete Cramp deficiency in chondrocytes failed to decrease catabolic gene expression upon IL-1β stimulation. Instead, genetic deletion of Cramp significantly worsened OA cartilage degradation in both MIA- and DMM-induced models. The detrimental phenotype observed in Cramp-deficient mice results from enhanced chondrocyte apoptosis. Therefore, even minimal Cramp expression appears essential for maintaining catabolic balance and preventing chondrocyte apoptosis in OA cartilage. Collectively, our data indicate that Cramp may exert multifaceted effects on OA pathogenesis by modulating catabolic pathways and apoptosis.