APP promotes osteoblast survival and bone formation by regulating mitochondrial function and preventing oxidative stress
Open accessAbstract
Amyloid precursor protein (APP) is ubiquitously expressed in various types of cells including bone cells. Mutations in App gene result in early-onset Alzheimer’s disease (AD). However, little is known about its physiological function in bone homeostasis. Here, we provide evidence for APP’s role in promoting bone formation. Mice that knocked out App gene (APP−/−) exhibit osteoporotic-like deficit, including reduced trabecular and cortical bone mass. Such a deficit is likely due in large to a decrease in osteoblast (OB)-mediated bone formation, as little change in bone resorption was detected in the mutant mice. Further mechanical studies of APP−/−OBs showed an impairment in mitochondrial function, accompanied with increased reactive oxygen species (ROS) and apoptosis. Intriguingly, these deficits, resemble to those in Tg2576 animal model of AD that expresses Swedish mutant APP (APPswe), were diminished by treatment with an anti-oxidant NAC (n-acetyl-l-cysteine), uncovering ROS as a critical underlying mechanism. Taken together, these results identify an unrecognized physiological function of APP in promoting OB survival and bone formation, implicate APPswe acting as a dominant negative factor, and reveal a potential clinical value of NAC in treatment of AD-associated osteoporotic deficits.
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Previous studies have shown abundant APP protein expression in bone and bone marrow cells, such as macrophages, osteoclasts and osteoblasts in WT mice.
“Previous studies have shown abundant APP protein expression in bone and bone marrow cells, such as macrophages, osteoclasts and osteoblasts in WT mice79,80.”
From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [79]
The Results section (‘Osteoporotic deficits in APP−/− mice’; page unavailable) reports APP detection in mouse bone-marrow cells, including BMSCs and BMMs, and the Discussion reports higher APP levels in osteoblasts than in BMSCs. The paper examines osteoclasts, but the passages found do not establish abundant APP protein expression in osteoclasts specifically. (LLM, conf=0.84)
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BackgroundMETTL5 deficiency impairs osteogenesis through OSER1-dependent antioxidant regulation
Lei, K., Yin, Q., Li, Q.-W., Wang, Q., Zhang, Z., Xue, F., Xu, R.-S., Zhou, X., Peng, L., Kokabu, S., et al. (2026) · JCI Insight · doi:10.1172/jci.insight.194068 · Cited by 3
“JCI Insight 2026;11(9):e194068 https://doi.org/10.1172/jci.insight.194068 redox balance in osteogenesis (19).”
InfluentialWang, N., Shen, X., Huang, H., Zhao, R., Jiwa, H., Li, Z., Li, P., Ye, J., & Zhou, Q. (2024) · Genes & Diseases · doi:10.1016/j.gendis.2024.101317 · Cited by 2 · see citing works
“16,17 18 e 21 AICD is susceptible to degradation by various enzymes present in the cytoplasm.”
Beyond Structure: The Interplay of Bone and Brain During Alzheimer's Disease
Pinnamaneni, A., Akkiraju, A., Park, H. I., Ch, R. S. R., V, Ayalasomayajula, V., Bandela, M., Kaipa, S., Khosla, S., Zeineh, M., & Suryadevara, V. (2025) · Comprehensive Physiology · doi:10.1002/cph4.70075 · Cited by 2 · see citing works
“APP knockout (APP − / − ) mice demonstrate severe osteo-blast dysfunction and oxidative stress, implicating APP as a necessary factor for bone maintenance (Pan et al. 2018).”
Sosa-Díaz, E., Reyes-Gopar, H., de Anda-Jáuregui, G., & Hernández-Lemus, E. (2025) · Nutrients · doi:10.3390/nu17030429 · Cited by 2 · see citing works
“GAS and APP maintenance in non parenchymal cell types from senescent cells could play a role in bone homeostasis promoted by vitamin D, promoting bone formation [89,90].”
Metabolic (re)programming in skeletal stem cell populations
Rajković, M., Bogosavljević, N., Vujačić, M., & Trivanović, D. I. (2024) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2024.100548 · Cited by 1 · see citing works
Zhu, M., Zeiss, C. J., Hamrick, M. W., Weinstein, R. S., Sun, B.-H., Brotto, M., Liu, X., Siu, E., Huttner, A., Tommasini, S. M., et al. (2024) · Bone · doi:10.1016/j.bone.2024.117086 · Cited by 2 · see citing works
Musculoskeletal and Psychological Rehabilitation
Jethwa, J. T. (2023) · Indian Journal of Orthopaedics · doi:10.1007/s43465-023-01072-5 · Cited by 2 · see citing works
“ROS have been proven to cause osteoblast apoptosis, which results in reduced bone production [10].”
Presenilin L166P Mutation, a Model of Familial Alzheimer's Disease, Leads to Early Onset Bone Loss
Suryadevara, V., Krehbial, C. J., Valiya, A. K., Vang, M., Balanta-Melo, J., Eleniste, P. P., Posritong, S., Hong, J.-M., Chester, K., Pagnotti, G., et al. (2026) · Comprehensive Physiology · doi:10.1002/cph4.70097 · Cited by 1 · see citing works
“Published literature has shown that APP promotes osteoblast survival and bone formation, specifically by altering mitochondrial ROS which contributes to apoptosis (Pan et al. 2018).”
INSIDER: Interpretable sparse matrix decomposition for RNA expression data analysis
Zhao, K., Huang, S., Lin, C., Sham, P., So, H.-C., & Lin, Z.-X. (2024) · PLoS Genetics · doi:10.1371/journal.pgen.1011189 · Cited by 1 · see citing works
Self-citationINSIDER: Interpretable Sparse Matrix Decomposition for Bulk RNA Expression Data Analysis
Zhao, K., Huang, S., Lin, C., Sham, P., So, H.-C., & Lin, Z.-X. (2022) · bioRxiv · doi:10.1101/2022.11.10.515904 · Cited by 1
“Moreover, a degree of comorbidity of AD and osteoporosis is also supported by epidemiological studies [36].”
ResultSelf-citationSpatial transcriptomics reveals microenvironmental heterogeneity in osteoarthritic subchondral bone
Lin, W.-Q., Xiao, X.-Y., Tian, D., Gong, Y., Huang, L., Kim, W.-K., Islam, M. A., Pan, G.-H., Zou, B.-H., Luo, Z., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-77518-9
“APP-APLP2 showed spatial colocalization in sclerotic microenvironments, consistent with trans-adhesive APP-family assemblies that stabilize cell-cell contacts and organize membrane-proximal signaling within osteogenic/stromal compartments 39 – 41 .”
Chen, H.-C., Li, X.-Q., Fan, X., Chang, C., Zhou, J.-M., Wang, D.-S., Yang, S.-W., Yang, Q.-H., Cao, Z.-P., Luan, P., et al. (2026) · Animals · doi:10.3390/ani16203189
“APP has been shown to promote osteoblast survival and bone formation, suggesting a potential role in maintaining bone homeostasis [30].”
Cadmium exposure triggers a functional switch of APP to drive joint degeneration
Fan, Y.-B., Shi, M.-Q., Zou, S.-Y., Lu, Z.-Q., Gou, X., Zhu, J.-C., & Feng, S.-T. (2026) · Molecular Medicine · doi:10.1186/s10020-026-01603-4
Wang, B.-H., & Dong, B. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1846467
“PGC-1 α and APP further support a close link between impaired osteogenesis, mitochondrial dysfunction, and osteoporosis progression by regulating mitochondrial biogenesis, osteoblast differentiation, and oxidative stress (Yu et al., 2018; Pan et al., 2018).”
Self-citationShukla, K., Zhang, Z., Plafker, K. S., Matsuzaki, S., Salinas-Salinas, C., Thomason, Y. M., Houmam, S., Barber, D., Faakye, A., Humphries, K. M., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.20.700642
- Authors
- Pan, J.-X., Tang, F., Xiong, F., Xiong, L., Zeng, P., Wang, B., Zhao, K., Guo, H., Shun, C., Xia, W.-F., Mei, L., & Xiong, W.-C.
- Affiliations
- Augusta University (US)
- Tongji Hospital (CN)
- Wuhan Union Hospital (CN)
- Corresponding author
- Xiong, Wen-Cheng
- Venue
- Cell Death & Disease
- Published
- 2018-10-22
- Volume
- 9
- Issue
- 11
- Pages
- 1077-1077
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC6197195
- OpenAlex
- W2898009164
- Cited by
- 59
- References
- 49
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 14 · 2023: 8 · 2022: 5 · 2021: 8 · 2020: 4 · 2019: 9
- FWCI
- 1.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (AG045781)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- amyloid precursor protein, osteoblast survival, bone formation, bone homeostasis, osteoporosis, mitochondrial function, oxidative stress, reactive oxygen species, apoptosis, APPswe, Tg2576 mice, Alzheimer's disease, N-acetylcysteine, dominant negative effect, trabecular bone mass, cortical bone mass
- MeSH terms
- Acetylcysteine, Alzheimer Disease, Animals, Antioxidants, Bone and Bones, Bone Resorption, Brain, Cells, Cultured, Disease Models, Animal, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Osteoblasts, Osteogenesis, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Mice
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