# Pathogenesis of LRP6 High Bone Mass

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2021 · $207,900

## Abstract

Project Summary
 LRP5 encodes low-density lipoprotein receptor-related protein 5 (LRP5). When LRP5 with a Frizzled
receptor join on the surface of an osteoblast (OB) and bind a member of the Wnt family of ligands, canonical
Wnt/β-catenin signaling occurs and increases bone formation. Eleven heterozygous gain-of-function missense
mutations within LRP5 are known to prevent the LRP5 inhibitory ligands sclerostin and dickkopf1 from attaching
to LRP5's first β-propeller, and thereby explain the rare autosomal dominant (AD) skeletal disorder “high bone
mass” (HBM). LRP6 is a cognate co-receptor of LRP5 and similarly controls Wnt signaling in osteoblasts, yet
the consequences of increased LRP6-mediated signaling remained unknown, until now. We investigated two
multi-generational American families manifesting the clinical and routine laboratory features of LRP5 HBM but
without an LRP5 defect and instead carrying a heterozygous LRP6 missense mutation (c.602C>T, p.A201V or
c.553A>C, p.N185H). In both families, the LRP6 mutation co-segregated with striking generalized osteosclerosis
and hyperostosis. Clinical features shared by the seven LRP6 HBM family members and ten LRP5 HBM patients
included a broad jaw, torus palatinus, teeth encased in bone and, reportedly, resistance to fracturing and inability
to float in water. However, there were significant clinical differences between our LRP5 and LRP6 families. DXA
mean BMD Z-scores in LRP6 HBM versus LRP5 HBM were somewhat higher at the lumbar spine, and increased
with age only in the LRP6 HBM families. Absence of adult maxillary lateral incisors was reported by some
members in both LRP6 HBM families, but was not noted in LRP5 HBM. Hence, we have discovered mutations
of LRP6 that cause a dento-osseous disorder similar to LRP5 HBM, but with some differences. We want to
elucidate the mechanism of action for these LRP5 and LRP6 HBM mutations in both OBs and osteoclasts (OCs),
since recent data shows that WNT signaling is important in inhibiting OC development and function. We propose
to make induced pluripotent stem cells (iPSCs) from LRP5 and LRP6 HBM patient-derived cells (either kidney
cells from urine or blood leukocytes). We will then compare and contrast OB development and function using
LRP5 and LRP6 patient-derived iPSCs, along with control iPSCs. We will also assess Wnt signaling in OBs, for
both mutant cell types to look for subtle differences in the mechanism of disease. We will also assess the impact
of LRP5 and LRP6 mutations on OC development and function using patient-derived iPSCs, and initiate Wnt
signaling studies in both mutant cell types. Our findings will lead to a better understanding of WNT signaling in
bone development and turnover, and help guide development of better treatments for human diseases of both
high and low (i.e. osteoporosis) bone mass.

## Key facts

- **NIH application ID:** 10127954
- **Project number:** 1R21AR077291-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** STEVEN R MUMM
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $207,900
- **Award type:** 1
- **Project period:** 2021-07-06 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127954

## Citation

> US National Institutes of Health, RePORTER application 10127954, Pathogenesis of LRP6 High Bone Mass (1R21AR077291-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10127954. Licensed CC0.

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