Biochemical pharmacologyJul 31, 2026

How a cell growth pathway increases cholesterol receptor and fat buildup in bone cells during hip bone tissue death after injury

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 3, 2026

Abstract

Severe hypoxia in trauma-induced osteonecrosis of the femoral head leads to oxidized lipid accumulation and cell death in osteocytes.

Hypoxia activates the mTORC1 pathway, which is associated with increased levels of oxidized lipids in osteocytes.
This activation promotes the upregulation of SREBP2, leading to enhanced synthesis of LDL receptors (LDLR) and reduced degradation of LDLR.
Accumulation of LDL and oxidized LDL in osteocytes may initiate a cascade resulting in cell death through the lacunar-canalicular network.
Inhibition of mTORC1 with rapamycin has been shown to reverse lipid accumulation and the associated cell death in osteocytes.

Simplified

Osteocyte apoptosis induced by hypoxia and ischemia represents a central pathological hallmark of trauma-induced osteonecrosis of the femoral head (TIONFH). Increasing evidence further implicates lipid metabolism disturbance in femoral heads as a critical contributor. However, the underlying molecular mechanisms, especially the lipid metabolism in osteocytes, remain poorly defined. We demonstrate for the first time that severe hypoxia in TIONFH drives oxidized lipid accumulation and cell apoptosis in osteocytes via coordinated activation of the mTORC1/LDLR axis. In vitro and in vivo studies prove that hypoxia elicits LDL/ox-LDL accumulation by activating mTORC1, which promotes SREBP2 upregulation and SCAP-SREBP2 translocation to the Golgi complex, thereby enhancing LDLR synthesis; while concurrently suppressing PCSK9-mediated LDLR degradation, ultimately resulting in excessive LDL uptake. Under hypoxic conditions, intracellular LDL/ox-LDL tends to propagate through the lacunar-canalicular network to initiate a cascade of osteocyte death. Notably, pharmacological inhibition of mTORC1 with rapamycin effectively reverses these effects and osteocyte death cascade. Collectively, our findings define a previously unrecognized mTORC1/LDLR axis linking hypoxia to lipid accumulation and osteocyte apoptosis in TIONFH, and highlight a potential target for early-stage TIONFH prevention and treatment.

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Competing interests

No financial or personal ties reported.

PubMed

How a cell growth pathway increases cholesterol receptor and fat buildup in bone cells during hip bone tissue death after injury

Abstract

Full Text

Funding

Competing interests

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