Upregulating a Key Cartilage Factor Leads to Osteoarthritis

Researchers have found that sustained expression of excess hypoxia-inducible factor (HIF)-1α leads to unwanted formation of blood vessels (angiogenesis) that destroys cartilage and causes osteoarthritis.

A necessary but destructive factor

Being required for extracellular matrix (ECM) construction and energy in the absence of oxygen, HIF-1α is necessary for cartilage-building cells (chondrocytes), which normally live in a low-oxygen environment, to function properly [1]. However, excessive HIF-1α is commonly found in osteoarthritic joints [2], and some previous work has linked it to angiogenesis in the cartilage, placing blood vessels where none should exist [3].

Still, given its beneficial nature under normal circumstances, researchers had struggled to determine whether upregulated HIF-1α was a protective reaction to damage or a source of damage itself. We have reported on previous work finding that HIF-1α has benefits in the spine by inhibiting iron-related cellular death (ferroptosis). That study, however, focused on nucleus pulposus cells. This research focuses on chondrocytes and their compartments, and what it has to say about excessive HIF-1α is nothing good.

Results in mice and people

In this paper’s first study, the researchers examined cartilage and synovium derived from osteoarthritis patients. Samples harvested from severely damaged areas were considerably richer in HIF-1α than samples from undamaged areas. Vascular endothelial growth factor (VEGF), which promotes angiogenesis, was also significantly upregulated in the damaged areas.

Comparing joint samples from 6-month-old and 24-month-old mice found similar results, with both compounds being upregulated in the older mice. Artificially inducing osteoarthritis in 3-month-old mice through surgery caused similar upregulations, with the cartilage taking longer to exhibit long-term upregulation than the synovium, where it occurred immediately.

Mice that express more HIF-1α withstand more pain

The researchers then used a population of mice that were genetically engineered to express excessive HIF-1α, and induced arthritis into one of their knees. Compared to wild-type mice, these altered mice endured more pain and had greater joint deterioration. Interestingly, the altered mice expressed both more building-related (anabolic) and destruction-related (catabolic) factors compared to the wild-type mice. According to the researchers, “this indicates that sustained HIF-1α activation drives a ‘metabolic paradox’ where compensatory synthetic efforts are overwhelmed by parallel catabolic signaling.”

Even without induced arthritis, the mice modified to express more HIF-1α began to develop it at 9 months of age anyway, with abnormal bone remodeling and a loss of cartilage. By 12 months of age, these mice had developed severe osteoarthritis, including complete erosion of cartilage. Therefore, excessive HIF-1α is, by itself, sufficient to drive the disease.

Progression is determined by tissue expression

Osteoarthritis progression in these animals was found to be driven by a loss of the hypoxic environment where chondrocytes normally live. At 9 months of age, this loss of hypoxia coincided with significant increases in cellular senescence as well, and markers of senescence were found throughout the tissues at 12 months of age. This was preceded by the ‘metabolic paradox’ that the researchers had discovered in the previous experiment; at 6 months of age, these mice exhibited increases in both anabolic and catabolic factors, “irreversibly tipping the cartilage from a state of frustrated repair into overwhelming, chronic degeneration.” Similar results were found when a population of wild-type mice was injected with mRNA causing excessive HIF-1α to be produced in the cartilage.

The authors turned to a different type of genetically engineered mouse, which expresses excessive HIF-1α only in the superficial tissues around the joint. These mice took longer to show disease symptoms: they experienced inflammation in the joints at 12 months of age, and at 15 months of age, they had developed full-blown osteoarthritis. There was significant angiogenesis in their joints, along with significant upregulation of inflammatory factors. Their osteoarthritis occurred alongside the suppression of anabolic factors and large upregulations of catabolic ones.

The researchers are clear that there is a substantial difference between transiently upregulated and normally fluctuating HIF-1α and the sustained increases in HIF-1α that lead to, and exacerbate, osteoarthritis. They describe it as a long-term stressor that ages the joints over time, and they note that instead of attempting to bolster it in tissues as any kind of treatment, it may make sense to attempt to remove it from the joints of older patients instead.

Literature

[1] Sophia Fox, A. J., Bedi, A., & Rodeo, S. A. (2009). The basic science of articular cartilage: structure, composition, and function. Sports health, 1(6), 461-468.

[2] Qing, L., Lei, P., Liu, H., Xie, J., Wang, L., Wen, T., & Hu, Y. (2017). Expression of hypoxia-inducible factor-1α in synovial fluid and articular cartilage is associated with disease severity in knee osteoarthritis. Experimental and therapeutic medicine, 13(1), 63-68.

[3] Caliogna, L., Berni, M., Torriani, C., Mancuso, M. E., Di Minno, M. N. D., Brancato, A. M., … & Pasta, G. (2024). Pathogenesis of osteoarthritis, rheumatoid arthritis, and hemophilic arthropathy: The role of angiogenesis. Haemophilia, 30(6), 1256-1264.