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Peer-reviewedCC BYCell Death and Disease

ITGBL1 inhibits obesity and osteoporosis by maintaining adipogenic and osteogenic differentiation balance via the NEDD4–PPARγ–RUNX2 axis

  • Hao Tan1
  • Jia-Shuai Zhong1
  • Lin-Sen Li1
  • Rui Zhang1,2
  • Wen-Xin Yan1
  • Tian-Hao Zhou1
  • Qing-Shan Wang1,2
  • Yu-Mei Feng3,4
4 affiliations
  1. 1Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China.
  2. 2Key Laboratory of Cancer Immunology and Biotherapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
  3. 3Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China. [email protected].
  4. 4Key Laboratory of Cancer Immunology and Biotherapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China. [email protected].
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Abstract

Obesity and osteoporosis are two major public health concerns. Dysregulation of mesenchymal stem cell (MSC) lineage commitment has been closely linked to an imbalance between adipogenic and osteogenic differentiation, which leads to abnormal lipid accumulation and impaired bone homoeostasis. However, as the underlying mechanisms remain unclear, effective treatment options for these two tightly linked diseases are still lacking. Herein, integrin subunit β-like 1 (ITGBL1) is identified as a key regulator of the adipogenic and osteogenic lineage commitment of MSCs. ITGBL1 is downregulated in MSCs from mouse models of high-fat diet (HFD)-induced obesity and ovariectomy (OVX)-induced osteoporosis. ITGBL1 deficiency promotes the adipogenic differentiation of bone marrow-derived MSCs, adipose-derived MSCs and adipogenic precursor cells while impairing the osteogenic differentiation of bone marrow-derived MSCs and osteogenic precursor cells. Mechanistically, ITGBL1 promotes the NEDD4-mediated ubiquitination and proteasomal degradation of PPARγ. ITGBL1 deficiency stabilizes PPARγ to activate adipogenic transcriptional programs. PPARγ further undergoes reciprocal transrepression with RUNX2 in specific cellular contexts, and these transcription factors transrepress and transactivate ITGBL1 in osteogenic and adipogenic lineage precursor cells, respectively. Thus, ITGBL1, PPARγ and RUNX2 constitute an interconnected regulatory network‌ that governs the lineage commitment of MSCs. Therapeutically, adeno-associated virus serotype 9-mediated ITGBL1 supplementation significantly alleviates obesity and/or osteoporosis in HFD-fed mice, OVX mice and systemic ITGBL1-deficient mice. Our findings reveal that ITGBL1 is crucial for maintaining the balance between the adipogenic and osteogenic differentiation of MSCs and has notable medicinal effects for the prevention and treatment of obesity and osteoporosis.

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Cite

BibTeXRIS
BibTeX
@article{tan2026itgbl1,
  title = {{ITGBL1 inhibits obesity and osteoporosis by maintaining adipogenic and osteogenic differentiation balance via the NEDD4–PPARγ–RUNX2 axis}},
  author = {Hao Tan and Jia-Shuai Zhong and Lin-Sen Li and Rui Zhang and Wen-Xin Yan and Tian-Hao Zhou and Qing-Shan Wang and Yu-Mei Feng},
  journal = {Cell Death and Disease},
  year = {2026},
  month = sep,
  doi = {10.1038/s41419-026-09220-z},
  url = {https://doi.org/10.1038/s41419-026-09220-z},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - ITGBL1 inhibits obesity and osteoporosis by maintaining adipogenic and osteogenic differentiation balance via the NEDD4–PPARγ–RUNX2 axis
AU  - Hao Tan
AU  - Jia-Shuai Zhong
AU  - Lin-Sen Li
AU  - Rui Zhang
AU  - Wen-Xin Yan
AU  - Tian-Hao Zhou
AU  - Qing-Shan Wang
AU  - Yu-Mei Feng
PY  - 2026
DA  - 2026/09/01
JO  - Cell Death and Disease
DO  - 10.1038/s41419-026-09220-z
UR  - https://doi.org/10.1038/s41419-026-09220-z
AB  - Obesity and osteoporosis are two major public health concerns. Dysregulation of mesenchymal stem cell (MSC) lineage commitment has been closely linked to an imbalance between adipogenic and osteogenic differentiation, which leads to abnormal lipid accumulation and impaired bone homoeostasis. However, as the underlying mechanisms remain unclear, effective treatment options for these two tightly linked diseases are still lacking. Herein, integrin subunit β-like 1 (ITGBL1) is identified as a key regulator of the adipogenic and osteogenic lineage commitment of MSCs. ITGBL1 is downregulated in MSCs from mouse models of high-fat diet (HFD)-induced obesity and ovariectomy (OVX)-induced osteoporosis. ITGBL1 deficiency promotes the adipogenic differentiation of bone marrow-derived MSCs, adipose-derived MSCs and adipogenic precursor cells while impairing the osteogenic differentiation of bone marrow-derived MSCs and osteogenic precursor cells. Mechanistically, ITGBL1 promotes the NEDD4-mediated ubiquitination and proteasomal degradation of PPARγ. ITGBL1 deficiency stabilizes PPARγ to activate adipogenic transcriptional programs. PPARγ further undergoes reciprocal transrepression with RUNX2 in specific cellular contexts, and these transcription factors transrepress and transactivate ITGBL1 in osteogenic and adipogenic lineage precursor cells, respectively. Thus, ITGBL1, PPARγ and RUNX2 constitute an interconnected regulatory network‌ that governs the lineage commitment of MSCs. Therapeutically, adeno-associated virus serotype 9-mediated ITGBL1 supplementation significantly alleviates obesity and/or osteoporosis in HFD-fed mice, OVX mice and systemic ITGBL1-deficient mice. Our findings reveal that ITGBL1 is crucial for maintaining the balance between the adipogenic and osteogenic differentiation of MSCs and has notable medicinal effects for the prevention and treatment of obesity and osteoporosis.
SN  - 2041-4889
ER  -