ABSTRACT
Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA, the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis; however, it conferred high cardiovascular risk in clinical trials. Furthermore, romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.
ABSTRACT
El lupus eritematoso sistémico es el prototipo de las enfermedades autoinmunes no órgano-específicas, con un curso fluctuante entre periodos de remisión y crisis. La complejidad de sus mecanismos fisiopatológicos mantiene la necesidad de desarrollar nuevos tópicos de investigación que faciliten su entendimiento y generen potenciales blancos terapéuticos. La vía de señalización Wnt y su principal inhibidor la protema Dickkopf-1 tienen un rol trascendental en fenómenos biológicos como la homeostasis ósea. Sin embargo, estudios recientes en lupus eritematoso sistémico han permitido reconocer otros procesos extraóseos regulados por la proteína Dickkopf-1. Entre ellos: la preservación de la integridad de las membranas glomerulares a nivel renal, reversión de rasgos de senescencia de células mesenquimales de interés en la optimización de los planes de trasplante como medida terapéutica; y la homeostasis articular. Alrededor de estos resultados han de suscitarse nuevas investigaciones sobre la proteína Dickkopf-1 y lupus eritematoso sistémico, que consoliden la información obtenida dado el gran potencial clínico y terapéutico que implica.
Systemic lupus erythematosus is the prototype of non-organ specific autoimmune diseases, with a fluctuating course between remission and crisis. The complexity of pathophysiological mechanisms opens up the possibility to develop multiple research topics to facilitate their understanding and generate potential therapeutic targets. The Wnt signalling pathway and its main inhibitor, Dickkopf-1 protein, have a major role in biological phenomena, such as bone homeostasis. However, recent studies have enabled other extra-osseous processes regulated by Dickkopf-1 to be recognised. These include: preserving the integrity of kidney glomerular membranes, senescence reversal characteristics of mesenchymal cells of interest in optimising transplantation plans as a therapeutic measure, and joint homeostasis. Some of these results have led to further research into Dickkopf-1 and systemic lupus erythematosus, in order to consolidate the information obtained given the great clinical and therapeutic potential involved.