Nature Communications: Mechanism of abnormal cholesterol metabolism leading to osteoarthritis

On November 21, 2022, researcher Hu Xiaoqing/Professor Ao Yingfang's research team from the Department of Sports Medicine of Peking University Third Hospital (Peking University Institute of Sports Medicine) published an article entitled "Cholesterol-induced LRP3 downregulation promotes cartilage" in the international authoritative journal Nature Communications degeneration in osteoarthritis by targeting Syndecan-4"
.

Osteoarthritis (OA) is a common joint degenerative disease with clinical manifestations of joint pain, limited mobility, and joint deformity
.
At present, the clinical treatment of OA is limited to weight reduction, symptomatic treatment and joint replacement, and there is a lack of effective intervention strategies
for the cause.
Therefore, exploring the pathogenesis of OA and finding effective therapeutic targets has always been a hot spot and difficult point in the field
.

The main pathological features of OA are articular cartilage degeneration and its homeostatic imbalance
in extracellular matrix metabolism.
In the past, it was believed that OA cartilage degeneration was associated with aging, trauma and abnormal stress, but the available evidence suggests that metabolic disorders and inflammatory aging play an important role
in OA cartilage degeneration.
Hypercholesterolemia due to abnormal cholesterol metabolism has been shown to be an independent risk factor
for OA.
The incidence of hypercholesterolemia in OA patients was 21.
9%, and the pain and OA severity scores of OA patients with hypercholesterolemia were higher than those in the control group
.
At the same time, studies have found that the administration of lipid-lowering drugs can delay the disease progression
of OA.
However, the specific molecular mechanism of abnormal cholesterol metabolism in OA cartilage degeneration still needs to be studied in depth
.

This study found that a high-cholesterol diet and exogenous cholesterol stimulation can cause dysregulation of extracellular matrix metabolism of chondrocytes, resulting in OA; During this process, the expression level of lipoprotein receptor related protein 3 (LRP3), a gene related to cholesterol metabolism in chondrocytes, was significantly reduced
。 Furthermore, the role of LRP3 in regulating the balance of extrachondrocytes matrix metabolism, inhibiting OA cartilage degeneration and targeted treatment of OA was investigated by lentiviral target gene intervention vector, gene knockout mice and high-throughput transcriptome sequencing, and it was found that the loss of LRP3 in adult mouse articular chondrocytes would lead to OA, and overexpression of LRP3 protein could inhibit cartilage
degeneration by improving the extrachondrocytes matrix metabolism 。 Mechanistic studies have found that the gene multiligand proteoglycan 4 (SDC4), a gene related to extracellular matrix degradation, is involved in regulating the metabolism of the extracellular matrix and the degeneration of
OA cartilage as a downstream molecular target of LRP3.
This paper comprehensively elucidates the abnormal cholesterol metabolism, the interaction relationship between LRP3 and SDC4, and their roles and mechanisms in OA cartilage degeneration, which provides new potential intervention targets for the treatment of OA
.

Cholesterol-LRP3-SDC4 regulates the occurrence of OA

Dr.
Cao Chenxi and Dr.
Shi Yuanyuan of the Department of Sports Medicine are the co-first authors of the paper, and Assistant Researcher Cheng Jin, Hu Xiaoqing and Ao Yingfang are the co-corresponding authors
of the paper.
The research results were supported
by the National Natural Science Foundation of China and the Beijing Municipal Natural Science Foundation.