# Membrane Palmitoylated Protein 7 is Required for Osteogenesis and is Linked with Bone Mineralization and Osteoporosis: The Functional Evaluation of GEFOS GWAS Hit

## TL;DR

This study shows that MPP7, a protein linked to bone health, is important for bone formation and its absence can lead to osteoporosis.

## Contribution

The study identifies MPP7 as a critical gene for osteogenesis and links it to osteoporosis through human and zebrafish data.

## Key findings

- MPP7 expression is reduced in osteoporotic bone tissue.
- MPP7 knockout in HOS cells impairs osteogenic differentiation and mineralization.
- MPP7 influences osteoblast function through cell polarity and adhesion.

## Abstract

Genome-wide association studies have identified multiple loci associated with bone mineral density, a major determinant of osteoporotic fracture risk. At one such locus, genetic, bioinformatic, and zebrafish knockout data strongly prioritize membrane palmitoylated protein 7 (MPP7) as a candidate gene, although its precise role in bone biology remains poorly defined. MPP7 encodes a member of the p55 Stardust family of membrane-associated guanylate kinase proteins, which are key regulators of epithelial cell polarity and junctional organization. Here, we investigated the functional role of MPP7 in bone biology. We found that MPP7 expression was significantly reduced—by approximately twofold—in bone tissue from osteoporotic patients compared with osteoarthritic patients and non-osteoporotic controls. Furthermore, we generated a CRISPR/Cas9-mediated MPP7 knockout in the human osteosarcoma HOS cell line and demonstrated that MPP7 deletion impairs osteogenic differentiation and completely abrogates mineralization through downregulation of ALPL expression. Knockout cells also displayed altered morphology, suggesting that MPP7 influences osteoblast function via effects on cell polarity and adhesion. Collectively, our findings, together with zebrafish genetic evidence, indicate that MPP7 plays a critical role in osteoblast differentiation and mineralization and may contribute to osteoporosis susceptibility in humans.

The online version contains supplementary material available at 10.1007/s00223-025-01439-w.