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

Abstract

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.