Role of CaV1.2 in Heterotopic Bone (HO) Formation
HO is an ectopic and pathological bone formation in extraskeletal tissues, including skeletal muscle, fascia, tendons and ligaments and can be induced by traumatic injury or in patients with genetic disorders. HO causes pain and reduces range of motion that progresses to immobilization and devastates health and daily life. No treatment is currently available and the precise pathophysiology of HO remains unknown. Therefore, better understanding of the cellular and molecular mechanisms that underlie the dysregulated mesenchymal progenitor cell commitment and of the signaling pathways involved in the disease processes is in need to identify therapeutic strategies that can prevent HO initiation and/or progression. Our laboratory has established a new HO mouse model, by which activating CaV1.2-TS mutant channel expression in tendon lineage cells induces Achilles tendon ectopic bone formation at 8 weeks old. It progresses more severe as age in the absence of injury. Notably, we have previously demonstrated that CaV1.2 is expressed in osteoprogenitor cells and increased Ca2+ influx via CaV1.2 has great osteogenic potential in both in vivo mouse models and in vitro BMSC culture system. Pharmacological approaches and allele ablation further demonstrated that Ca2+ influx via CaV1.2 channel is necessary for BMSC osteogenesis in culture. In this project, we aim to understand the role of Ca2+ signaling pathways via CaV1.2 and their cross-talk with other signaling pathways in mesenchymal cell fate determination during HO formation.
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