Articular Cartilage: Where it all started
The progenitor cells that form articular cartilage express a gene for a protein called NFATc1, which stops articular chondrocytes from developing too early in the joint.
- The First Affiliated Hospital of Xiamen University‐ICMRS Collaborating Center for Skeletal Stem Cell, State Key Laboratory of Cellular Stress Biology, Faculty of Medicine and Life Sciences, Xiamen University, China
- Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, China
Articular cartilage is a smooth white tissue that covers the ends of bones where they join together. It is essential for maintaining the mobility of bone joints. However, despite this important role, the tissue is susceptible to degeneration caused by trauma, disease or ageing. This can lead to conditions such as osteoarthritis, which can cause chronic pain and, in some cases, disability (Cui et al., 2020).
Reversing damage to articular cartilage remains a great challenge in musculoskeletal medicine. One way to tackle this issue is to better understand how articular cartilage forms during embryonic development, as this knowledge could help researchers to develop new methods for rebuilding cartilage. Yet, the origins of the main cells in cartilage, known as articular chondrocytes, and the identity of the genes that regulate their production remain unclear. Now, in eLife, Xianpeng Ge (Capital Medical University in Beijing) and colleagues – including Fan Zhang and Yuanyuan Wang as joint first authors – report new insights into the formation of articular chondrocytes (Zhang et al., 2023).
Previous research has shown that the gene NFATc1 helps to regulate the development of bones by controlling cells that absorb and form bone (Winslow et al., 2006). To find out if NFATc1 could also be involved in cartilage development, Zhang et al. used genetically modified mouse embryos, in which cells expressing NFATc1 were tagged with a fluorescent marker that allowed the researchers to track these cells and their offspring over time. This revealed that NFATc1 is expressed in a group of progenitor cells throughout embryonic and even postnatal development, and that these cells are responsible for generating most of the articular chondrocytes (Figure 1).
Figure 1
The role of NFATc1 in articular cartilage formation.
Zhang et al. identified a unique progenitor cell population in the knee joint of embryonic mice (left) that expresses a gene called NFATc1, which has previously been linked to bone formation and bone resorption. These progenitor (stem) cells are responsible for generating articular chondrocytes – the main cell type in articular cartilage – during both embryonic and postnatal development (right). Suppressing the activity of NFATc1 in these stem progenitor cells induces the formation of chondrocytes, which are essential for forming articular cartilage.
Further experiments in cells and embryonic mice revealed that the expression of NFATc1 decreased as the articular chondrocytes matured. Zhang et al. found that when the gene was removed from the cartilage progenitors, the maturation of chondrocytes was faster and the formation of articular cartilage in embryos was still supported. Consistent with this, when NFATc1 was overactivated, the progenitor cells could no longer mature into chondrocytes. This indicates that this gene negatively regulates the development of articular chondrocytes.
So far, it has been challenging to track how articular cartilage develops as most genetic markers cannot distinguish between the different cell types in the relevant tissues (Rux et al., 2019; Chijimatsu and Saito, 2019). The only exception is the gene Prg4, a widely used marker of articular cartilage progenitors. But since cells only start to express this gene at a later stage during development, the marker fails to track their movement during the earlier stages (Kozhemyakina et al., 2015). In contrast, NFATc1 is expressed early during articular cartilage development, and may therefore offer a better alternative for studying the origin of articular cartilage.
It was previously thought that NFATc1, together with another gene involved in cartilage formation, NFATc2, restricts the overgrowth of cartilage (also known as osteochondroma) at the sites where the ligaments insert into the bone. However, adjusting how much of either of those genes was removed from the mice’s progenitor cells could in fact determine the number and size of osteochondromas (Ge et al., 2016). This knowledge may be helpful in understanding how NFATc1 may suppress the formation of cartilage in certain diseases.
It has been suggested that both NFATc1 and NFATc2 are key suppressors of osteoarthritis, which is crucial for articular cartilage formation in mice (Greenblatt et al., 2013). However, when Zhang et al. used a different approach to delete these two genes, they observed the opposite effect – removing NFATc1 and NFATc2 enhanced chondrogenesis under pathological conditions. This suggests that researchers should carefully consider the genetic ablating tools they use when studying the role of progenitor cells in articular cartilage.
Moreover, it has been shown that adult skeletal stem cells expressing NFATc1 behave as bone-cell progenitors and contribute to the early stages of repair following a bone fracture (Yu et al., 2022). This highlights the complex pool of progenitor cells that express NFATc1, and how the fate of these progenitors changes during different periods of development as well as adulthood. More importantly, to date, it remains unclear whether these NFATc1-expressing progenitor cells fulfill stemness criteria in the skeleton, such as stem-cell transplantation (Debnath et al., 2018), or if these cells are able to generate functional articular cartilage.
Despite a lack of evidence confirming the stemness of NFATc1-expressing progenitor cells, the work of Zhang et al. offers researchers an additional genetic tool to detect and track the origins of articular chondrocytes. Moreover, their findings provide valuable insights into the mechanism of articular cartilage formation. If studies in human cells achieve similar results, this may help scientists to identify potential treatments of cartilage diseases, such as osteoarthritis.
References
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Mechanisms of synovial joint and articular cartilage developmentCellular and Molecular Life Sciences 76:3939–3952.https://doi.org/10.1007/s00018-019-03191-5
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Identification of a Prg4-expressing articular cartilage progenitor cell population in miceArthritis & Rheumatology 67:1261–1273.https://doi.org/10.1002/art.39030
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Joints in the appendicular skeleton: developmental mechanisms and evolutionary influencesCurrent Topics in Developmental Biology 133:119–151.https://doi.org/10.1016/bs.ctdb.2018.11.002
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Calcineurin/NFAT signaling in osteoblasts regulates bone massDevelopmental Cell 10:771–782.https://doi.org/10.1016/j.devcel.2006.04.006
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- Version of Record published: April 5, 2023 (version 1)
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Articular Cartilage: Where it all started
eLife 12:e87355.
https://doi.org/10.7554/eLife.87355
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Background:
Although there are several efficacious vaccines against COVID-19, vaccination rates in many regions around the world remain insufficient to prevent continued high disease burden and emergence of viral variants. Repurposing of existing therapeutics that prevent or mitigate severe COVID-19 could help to address these challenges. The objective of this study was to determine whether prior use of bisphosphonates is associated with reduced incidence and/or severity of COVID-19.
Methods:
A retrospective cohort study utilizing payer-complete health insurance claims data from 8,239,790 patients with continuous medical and prescription insurance January 1, 2019 to June 30, 2020 was performed. The primary exposure of interest was use of any bisphosphonate from January 1, 2019 to February 29, 2020. Bisphosphonate users were identified as patients having at least one bisphosphonate claim during this period, who were then 1:1 propensity score-matched to bisphosphonate non-users by age, gender, insurance type, primary-care-provider visit in 2019, and comorbidity burden. Main outcomes of interest included: (a) any testing for SARS-CoV-2 infection; (b) COVID-19 diagnosis; and (c) hospitalization with a COVID-19 diagnosis between March 1, 2020 and June 30, 2020. Multiple sensitivity analyses were also performed to assess core study outcomes amongst more restrictive matches between BP users/non-users, as well as assessing the relationship between BP-use and other respiratory infections (pneumonia, acute bronchitis) both during the same study period as well as before the COVID outbreak.
Results:
A total of 7,906,603 patients for whom continuous medical and prescription insurance information was available were selected. A total of 450,366 bisphosphonate users were identified and 1:1 propensity score-matched to bisphosphonate non-users. Bisphosphonate users had lower odds ratios (OR) of testing for SARS-CoV-2 infection (OR = 0.22; 95%CI:0.21–0.23; p<0.001), COVID-19 diagnosis (OR = 0.23; 95%CI:0.22–0.24; p<0.001), and COVID-19-related hospitalization (OR = 0.26; 95%CI:0.24–0.29; p<0.001). Sensitivity analyses yielded results consistent with the primary analysis. Bisphosphonate-use was also associated with decreased odds of acute bronchitis (OR = 0.23; 95%CI:0.22–0.23; p<0.001) or pneumonia (OR = 0.32; 95%CI:0.31–0.34; p<0.001) in 2019, suggesting that bisphosphonates may protect against respiratory infections by a variety of pathogens, including but not limited to SARS-CoV-2.
Conclusions:
Prior bisphosphonate-use was associated with dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations. Prospective clinical trials will be required to establish a causal role for bisphosphonate-use in COVID-19-related outcomes.
Funding:
This study was supported by NIH grants, AR068383 and AI155865, a grant from MassCPR (to UHvA) and a CRI Irvington postdoctoral fellowship, CRI2453 (to PH).
