Osteoarthritis affects nearly 500 million individuals worldwide, and no disease-modifying pharmacotherapies are currently available. This disease has long been viewed as a localized joint disorder driven mainly by mechanical wear and tear, but growing evidence suggests that it is also an aging-related systemic disorder involving metabolic and inflammatory crosstalk among multiple organs and tissues.
However, how metabolic tissues contribute to cartilage degeneration remains poorly understood. In particular, the roles of the liver and marrow adipose tissue (MAT), two metabolically active tissues that undergo marked changes during aging and metabolic dysfunction, have remained largely unknown.
In a study published in Bone Research, a team led by Prof. GUAN Min from the Shenzhen Institutes of Advanced Technology (SIAT) of the Chinese Academy of Sciences, along with collaborators, revealed a novel liver-MAT-cartilage axis that promotes cartilage degeneration in osteoarthritis through the complement component 3 (C3)-complement factor D (CFD)-membrane attack complexes (MAC) cascade, and demonstrated that targeting estrogen-related receptor alpha (ESRRA) in adipocytes interrupts this pathological crosstalk and alleviates osteoarthritis progression.
Researchers found that expanding bone marrow adipocytes (BMAds) responded to aging and metabolic stress by transcriptionally upregulating CFD via ESRRA, and steatotic hepatocytes released excessive complement C3 into the circulation. These two complement-related factors converged on joint cartilage where they activated the alternative complement pathway and promoted the deposition of MAC on chondrocytes. MAC accumulation then induced ERK1/2 hyperphosphorylation, mitochondrial fragmentation, and cellular senescence, leading to cartilage damage and osteoarthritis progression.
Besides, researchers revealed that ESRRA directly bound to the promoter of the Cfd gene and drove its expression in BMAds. Adipocyte-specific deletion of Esrra, as well as pharmacological inhibition of ESRRA with andrographolide, significantly reduced CFD production, blocked MAC deposition, preserved mitochondrial function in chondrocytes, and ultimately attenuated osteoarthritis in both spontaneous aging and surgically induced models.
In vitro co-culture experiments further demonstrated that the disruption of the C3-CFD-MAC cascade, either through ESRRA knockdown or pharmacological inhibition of CFD with Danicopan, protected chondrocytes from C3-triggered catabolism and cellular senescence.
This study reveals that osteoarthritis is not merely a joint problem, but a systemic disorder shaped by inter-organ communication among metabolic tissues. It provides new insight into how aging- and metabolism-associated changes in the liver and bone marrow niche contribute to cartilage degeneration. Targeting adipocyte ESRRA may represent a therapeutic strategy for aging- and metabolism-related osteoarthritis.