Reply to “Wnt/beta-catenin signaling inhibitors and nonalcoholic fatty liver disease: Potential therapeutic implications”

Karthik Shree Harini, Devaraj Ezhilarasan

Department of Pharmacology, Molecular Medicine and Toxicology Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences(SIMATS), Chennai, Tamil Nadu 600 077, India

TheAuthorReply:

We sincerely appreciated the interest of Polyzos et al., in our review article and sharing their improvised thoughts regarding the Wnt signaling modulators for the treatment of postmenopausal women with osteoporosis and nonalcoholic fatty liver disease (NAFLD).Several experimental studies have showed that the aberrant Wnt/β-catenin signaling promotes the development and/or progression of a variety of chronic liver diseases including NAFLD [1,2].Therefore, our review emphasized on the modulation of Wnt/β-catenin signaling and the role of its mediators in NAFLD progression.Given that NAFLD prevalence is constantly increasing, and that osteoporosis is associated with women over 50 years of age with NAFLD [3], there is an unmet need for an effective treatment.Sclerostin blocks the canonical Wnt signaling pathway of bone formation.Therefore, romosozumab, a humanized antisclerostin monoclonal antibody, was approved for the treatment of osteoporosis.Romosozumab binds to sclerostin, permitting the engagement of Wnt ligands with their co-receptors, resulting in an increase in bone formation and bone mineral density.

In Polyzos et al.’s perspective, antibodies against sclerostin and Dickkopf-1 (DKK-1) could be useful for the treatment of postmenopausal osteoporosis with NAFLD.We do agree that the DKK-1 antibody could be an efficient therapeutic direction to target Wnt signaling and to prevent NAFLD progression.The recent investigation [4], relating to the bispecific antibody targeting DKK-1 and sclerostin, is a leap forward in the therapeutic application.Concerning the established pathophysiological interaction of bone and liver, romosozumab could be a potential drug in the treatment of women who have increased sclerostin and postmenopausal osteoporosis, and NAFLD.Therefore, in osteoporosis, sclerostin can be targeted with its specific antibody since sclerostin is an inhibitor of bone formation.However, in NAFLD condition, decreased sclerostin levels were reported in NAFLD patients and mouse models [5,6].Rhee et al.[7]also observed decreased sclerostin levels in patients with an early stage of cirrhosis and increased sclerostin levels with advanced cirrhosis.Thus, at present, only a few reports suggest an increased sclerostin levels in NAFLD.Moreover, in the clinical setting, few epidemiological evidence indicates that NAFLD is associated with lower bone mineral density or osteoporosis in adults.An association between NAFLD and osteoporosis has not yet been established [8].Furthermore, the sclerostin level in osteoporotic women with NAFLD needs to be investigated in clinical subjects in an elaborate manner.

Acknowledgments

None.

CRediT authorship contribution statement

Karthik Shree Harini:Writing - original draft.Devaraj Ezhilarasan:Conceptualization, Funding acquisition, Writing - review &editing.

Funding

This study was supported by a grant from the Extramural Research Project - Indian Council of Medical Research, New Delhi, India (58/30/2020/PHA/BMS dtd.9.11.2021).

Ethical approval

Not needed.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.