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B4GALNT3 - a specific regulator of bone metabolism

Description: With increasing age of the population, Sweden and industrialized countries across the globe are facing a substantial increase in osteoporotic fractures, which account for considerable disease burden and costs. Sclerostin inhibition reduces fracture risk efficiently but has in some studies been associated with cardiovascular side effects.We have in preliminary studies demonstrated that the enzyme B4GALNT3 is a major regulator of bone-derived sclerostin, a mechanism involving specific glycosylation of sclerostin (LDN-glycosylation). We hypothesize that methods enhancing B4GALNT3 expression and thereby LDN-glycosylation of sclerostin may be a promising bone-specific osteoporosis drug target. The overall aim of this five-year project is to determine if B4GALNT3 is a key protein for bone metabolism without cardiovascular side effects.In project 1, we will determine the effect of B4GALNT3 mediated LDN-glycosylation of sclerostin on bone health and cardiovascular phenotypes using gene targeted mouse models and Mendelian randomization in humans. In project 2, we will determine the mechanism for B4GALNT3 to influence sclerostin levels. In project 3, we will determine if B4galnt3 regulation is involved in glucocorticoid-induced bone loss, osteoporosis caused by estrogen deficiency, and the bone-anabolic effect of loading.The proposed studies may establish B4GALNT3 as a novel bone-specific regulator of bone metabolism and result in improved prevention and treatment of osteoporosis.

Funder: Vetenskapsrådet

Amount: SEK 6,000,000

Funding type: research

Funder scheme: Project grant

Start date: 2023-01-01

End date: 2026-12-31

Investigator: Sofia Moverare Skrtic (lead)

Institution: University of Gothenburg

Topic: Bone health and osteoporosis research

Subfield: Orthopedics and Sports Medicine

Field: Medicine

Domain: Health Sciences