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Cited by 69Osteoarthritis Treatment and MechanismsBone Metabolism and DiseasesProteoglycans and glycosaminoglycans research

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Nerve growth factor receptor limits inflammation to promote remodeling and repair of osteoarthritic joints

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Zhao, Lan, Lai, Yumei, Jiao, Hongli, Huang, Jian·2024·Nature Communications
DOI 10.1038/s41467-024-47633-6PMC PMC11018862

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Abstract

Osteoarthritis (OA) is a painful, incurable disease affecting over 500 million people. Recent clinical trials of the nerve growth factor (NGF) inhibitors in OA patients have suggested adverse effects of NGF inhibition on joint structure. Here we report that nerve growth factor receptor (NGFR) is upregulated in skeletal cells during OA and plays an essential role in the remodeling and repair of osteoarthritic joints. Specifically, NGFR is expressed in osteochondral cells but not in skeletal progenitor cells and induced by TNFα to attenuate NF-κB activation, maintaining proper BMP-SMAD1 signaling and suppressing RANKL expression in mice. NGFR deficiency hyper-activates NF-κB in murine osteoarthritic joints, which impairs bone formation and enhances bone resorption as exemplified by a reduction in subchondral bone and osteophytes. In human OA cartilage, NGFR is also negatively associated with NF-κB activation. Together, this study suggests a role of NGFR in limiting inflammation for repair of diseased skeletal tissues.

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Figures

Fig. 1 Inflammation, neurogenesis, and bony remodeling during OA pathogenesis and progression. a, b Representative histology images of osteoarthritic knee joint sections stained by hematoxylin and eosin. The joints were collected 2 (a) or 4 weeks (b) after the DMM surgery. Arrowheads, inflamed synovial tissues. c Representative histology images of osteoarthritic knee joint sections stained by alcian blue/hematoxylin & orange G. The joints were collected 4 weeks after the DMM surgery. Arrowheads, synovial hyperplasia and osteochondral formation. Scale bar, 100 μm. n = 6 joints. d–h Representative immunohistochemistry (IHC) images of osteoarthritic knee joint sections stained by individual antibodies as shown. The joints were collected 4 weeks after the DMM surgery. Arrowheads positively IHC signals. Scale bar, 100 μm. Data are presented as mean values ± SD. n = 5 independent experiments. Unpaired two-sided Student’s t-test. ****p < 0.0001. Source data are provided as a Source Data file.
Fig. 1 Inflammation, neurogenesis, and bony remodeling during OA pathogenesis and progression. a, b Representative histology images of osteoarthritic knee joint sections stained by hematoxylin and eosin. The joints were collected 2 (a) or 4 weeks (b) after the DMM surgery. Arrowheads, inflamed synovial tissues. c Representative histology images of osteoarthritic knee joint sections stained by alcian blue/hematoxylin & orange G. The joints were collected 4 weeks after the DMM surgery. Arrowheads, synovial hyperplasia and osteochondral formation. Scale bar, 100 μm. n = 6 joints. d–h Representative immunohistochemistry (IHC) images of osteoarthritic knee joint sections stained by individual antibodies as shown. The joints were collected 4 weeks after the DMM surgery. Arrowheads positively IHC signals. Scale bar, 100 μm. Data are presented as mean values ± SD. n = 5 independent experiments. Unpaired two-sided Student’s t-test. ****p < 0.0001. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 2 NGFR is significantly upregulated in skeletal cells with committed osteochondral fates compared to progenitor cells at earlier stages. a, b Western results of NGFR in mouse cells (a) and in multiple human cell lines and RCS cells (b). n = 3 independent experiments. c Perturbations of NGFR validated the anti-NGFR antibody and confirmed NGFR proteins in C2C12. sg single guide RNA for CRISPR to mutate Ngfr. CRISPRa indicates CRISPR-mediated transcriptional activation of Ngfr. Control is the empty vector for CRISPRa. Note that sg1 targeting the promoter increased NGFR expression. n = 3 independent experiments. d TrkA had no detectable protein levels in skeletal cells. * Denotes non-specific bands detected. n = 3 independent experiments. e Ngfr mRNAs were markedly increased in mouse articular chondrocytes (AC), E14.5 limb bud cells, and C2C12 cells, compared to C3H10T1/2, ATDC5, and CD45- BMSCs. Data are presented as mean values ± SD. n = 3 independent experiments. One-way ANOVA. f, g NGFR mRNAs were significantly higher in human osteoblastic cell lines (hFOB1.19 and Saos-2) than in human mesenchymal stem cells (hMSC), whereas TrkA levels are significantly lower than NGFR in all examined cells. Data are presented as mean values ± SD. n = 3 independent experiments. One-way ANOVA. h, i NGFR proteins decreased with the dedifferentiation of committed skeletal cells induced by repeated passages. n = 3. *p < 0.05, **p < 0.01, ****p < 0.0001. Source data are provided as a Source Data file.
Fig. 2 NGFR is significantly upregulated in skeletal cells with committed osteochondral fates compared to progenitor cells at earlier stages. a, b Western results of NGFR in mouse cells (a) and in multiple human cell lines and RCS cells (b). n = 3 independent experiments. c Perturbations of NGFR validated the anti-NGFR antibody and confirmed NGFR proteins in C2C12. sg single guide RNA for CRISPR to mutate Ngfr. CRISPRa indicates CRISPR-mediated transcriptional activation of Ngfr. Control is the empty vector for CRISPRa. Note that sg1 targeting the promoter increased NGFR expression. n = 3 independent experiments. d TrkA had no detectable protein levels in skeletal cells. * Denotes non-specific bands detected. n = 3 independent experiments. e Ngfr mRNAs were markedly increased in mouse articular chondrocytes (AC), E14.5 limb bud cells, and C2C12 cells, compared to C3H10T1/2, ATDC5, and CD45- BMSCs. Data are presented as mean values ± SD. n = 3 independent experiments. One-way ANOVA. f, g NGFR mRNAs were significantly higher in human osteoblastic cell lines (hFOB1.19 and Saos-2) than in human mesenchymal stem cells (hMSC), whereas TrkA levels are significantly lower than NGFR in all examined cells. Data are presented as mean values ± SD. n = 3 independent experiments. One-way ANOVA. h, i NGFR proteins decreased with the dedifferentiation of committed skeletal cells induced by repeated passages. n = 3. *p < 0.05, **p < 0.01, ****p < 0.0001. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 3 NGFR is positively associated with osteochondral differentiation of human skeletal progenitor cells. a The UMAP plot of 5 weeks post conception (Carnegie stage 13) human limb bud and 8 WPC (CS22) human long bone. b The dot plot showing expressions of representative genes in each cluster. Clusters 0–4 can be grouped as skeletal lineage cells based on their expression of PRRX1 and PDGFRA. c The circle plot showing the aggregated cell–cell communication network and the total interaction strength (weights) between any two skeletal cell clusters. d Violin plots showing the cumulative expression of NGFR and PRRX1 in skeletal lineage cells of CS13 limb bud and CS22 long bone. e Characterization of the expression of NGFR, SOX9, RUNX2, and ACAN in each cluster of skeletal lineage cells, split by the groups of CS13 limb bud and CS22 long bone.
Fig. 3 NGFR is positively associated with osteochondral differentiation of human skeletal progenitor cells. a The UMAP plot of 5 weeks post conception (Carnegie stage 13) human limb bud and 8 WPC (CS22) human long bone. b The dot plot showing expressions of representative genes in each cluster. Clusters 0–4 can be grouped as skeletal lineage cells based on their expression of PRRX1 and PDGFRA. c The circle plot showing the aggregated cell–cell communication network and the total interaction strength (weights) between any two skeletal cell clusters. d Violin plots showing the cumulative expression of NGFR and PRRX1 in skeletal lineage cells of CS13 limb bud and CS22 long bone. e Characterization of the expression of NGFR, SOX9, RUNX2, and ACAN in each cluster of skeletal lineage cells, split by the groups of CS13 limb bud and CS22 long bone.CC BY · PubMed Central
Fig. 4 NGFR deficiency substantially reduces subchondral bone thickening and ectopic bone formation in osteoarthritic joints. a Aggrecan-CreER efficiently targets multiple osteochondral tissues in the osteoarthritic joints, including articular cartilage (AC), subchondral area (SC), and meniscus (m). Arrowhead, targeted cells in SC. Scale bar, 100 μm. n = 3 joints. b NGFR was induced in osteoarthritic joints. Both control (Ngfr floxed) and KO (NgfrAcan-CreER) mice were injected with tamoxifen weekly to ablate Ngfr, starting 10 days after the DMM surgery. Arrowheads: NGFR+ osteochondral cells. Scale bar, 100 μm. n = 5. c NGFR loss downregulated subchondral and ectopic bone formation (arrowheads) in osteoarthritic joints. Scale bar, 200 μm. n = 12 mice. d Representative μCT 3D images of control and KO joints with OA. Arrowheads, ectopic bone. e Representative μCT 3D images of ectopic bone growth around cartilage, meniscus and synovium, as well as quantification of ectopic BV. Data are presented as mean values ± SD. n = 12 mice. Unpaired two-sided Student’s t-test. f Representative μCT 2D images of subchondral bone and BV/TV quantification of subchondral bone underneath medial tibial plateau (inside the red circles). #, ectopic bone outside subchondral area. Scale bars: 1 mm. Data are presented as mean values ± SD. n = 12 mice. Unpaired two-sided Student’s t-test. **p < 0.01, ****p < 0.0001. Source data are provided as a Source Data file.
Fig. 4 NGFR deficiency substantially reduces subchondral bone thickening and ectopic bone formation in osteoarthritic joints. a Aggrecan-CreER efficiently targets multiple osteochondral tissues in the osteoarthritic joints, including articular cartilage (AC), subchondral area (SC), and meniscus (m). Arrowhead, targeted cells in SC. Scale bar, 100 μm. n = 3 joints. b NGFR was induced in osteoarthritic joints. Both control (Ngfr floxed) and KO (NgfrAcan-CreER) mice were injected with tamoxifen weekly to ablate Ngfr, starting 10 days after the DMM surgery. Arrowheads: NGFR+ osteochondral cells. Scale bar, 100 μm. n = 5. c NGFR loss downregulated subchondral and ectopic bone formation (arrowheads) in osteoarthritic joints. Scale bar, 200 μm. n = 12 mice. d Representative μCT 3D images of control and KO joints with OA. Arrowheads, ectopic bone. e Representative μCT 3D images of ectopic bone growth around cartilage, meniscus and synovium, as well as quantification of ectopic BV. Data are presented as mean values ± SD. n = 12 mice. Unpaired two-sided Student’s t-test. f Representative μCT 2D images of subchondral bone and BV/TV quantification of subchondral bone underneath medial tibial plateau (inside the red circles). #, ectopic bone outside subchondral area. Scale bars: 1 mm. Data are presented as mean values ± SD. n = 12 mice. Unpaired two-sided Student’s t-test. **p < 0.01, ****p < 0.0001. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 5 Loss of NGFR impairs bone formation in the context of inflammation. a NGFR ablation exacerbated the decrease of alkaline phosphatase activity induced by inflammatory cytokines. Vec, empty vector; sg2, CRISPR vector expressing single guide RNA 2 to mediate Ngfr deletion. n = 3. b, c NGFR perturbation altered SMAD1 and RANKL in TNF-α-treated cells. CRISPRa, CRISPR-mediated activation of Ngfr. n = 3 independent experiments. d–f NGFR deletion downregulated the marker gene expression in BMP-SMAD1 signaling. Data are presented as mean values ± SD. n = 2 independent experiments. Two-way ANOVA. g–i OA-induced upregulations of SMAD1 and p-SMAD1 were significantly attenuated by NGFR deficiency in OA joints. Data are presented as mean values ± SD. n = 5 independent experiments. Two-way ANOVA. j, k NGFR deletion downregulated RUNX2 protein level in OA joints. Scale bar: 100 μm. Data are presented as mean values ± SD. n = 5 independent experiments. Unpaired two-sided Student’s t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Source data are provided as a Source Data file.
Fig. 5 Loss of NGFR impairs bone formation in the context of inflammation. a NGFR ablation exacerbated the decrease of alkaline phosphatase activity induced by inflammatory cytokines. Vec, empty vector; sg2, CRISPR vector expressing single guide RNA 2 to mediate Ngfr deletion. n = 3. b, c NGFR perturbation altered SMAD1 and RANKL in TNF-α-treated cells. CRISPRa, CRISPR-mediated activation of Ngfr. n = 3 independent experiments. d–f NGFR deletion downregulated the marker gene expression in BMP-SMAD1 signaling. Data are presented as mean values ± SD. n = 2 independent experiments. Two-way ANOVA. g–i OA-induced upregulations of SMAD1 and p-SMAD1 were significantly attenuated by NGFR deficiency in OA joints. Data are presented as mean values ± SD. n = 5 independent experiments. Two-way ANOVA. j, k NGFR deletion downregulated RUNX2 protein level in OA joints. Scale bar: 100 μm. Data are presented as mean values ± SD. n = 5 independent experiments. Unpaired two-sided Student’s t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 6 NGFR loss-of-function further heightens inflammation-induced bone resorption. a–c NGFR deletion induced the Rankl/Opg mRNA ratio in TNF-treated cells. Vec, empty vector; sg2, CRISPR vector expressing single guide RNA 2 to mediate Ngfr deletion. Data are presented as mean values ± SD. n = 3 independent experiments. Two-way ANOVA. d, e TRAP staining and quantification of RAW264.7 cells cultured with medium conditioned by empty vector-infected or CRISPR-mediated Ngfr deletion cells. Scale bar: 80 μm. n = 3 independent experiments. Data are presented as mean values ± SD. Unpaired two-sided Student’s t-test. f, g TRAP staining and quantification of subchondral area in control and KO joints with OA. The lower edge of subchondral area is marked by the blue curves. The bottom panels are the enlargements of the upper images as indicated by the box, in order to show subchondral area in higher resolution. Arrowheads, positive TRAP staining in subchondral area. Scale bar: 100 μm. n = 7 independent experiments. Data are presented as mean values ± SD. Unpaired two-sided Student’s t-test. h, i IHC of RANKL in the osteoarthritic joints with NGFR deficiency. Scale bar: 100 μm. Data are presented as mean values ± SD. n = 5 independent experiments. Unpaired two-sided Student’s t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Source data are provided as a Source Data file.
Fig. 6 NGFR loss-of-function further heightens inflammation-induced bone resorption. a–c NGFR deletion induced the Rankl/Opg mRNA ratio in TNF-treated cells. Vec, empty vector; sg2, CRISPR vector expressing single guide RNA 2 to mediate Ngfr deletion. Data are presented as mean values ± SD. n = 3 independent experiments. Two-way ANOVA. d, e TRAP staining and quantification of RAW264.7 cells cultured with medium conditioned by empty vector-infected or CRISPR-mediated Ngfr deletion cells. Scale bar: 80 μm. n = 3 independent experiments. Data are presented as mean values ± SD. Unpaired two-sided Student’s t-test. f, g TRAP staining and quantification of subchondral area in control and KO joints with OA. The lower edge of subchondral area is marked by the blue curves. The bottom panels are the enlargements of the upper images as indicated by the box, in order to show subchondral area in higher resolution. Arrowheads, positive TRAP staining in subchondral area. Scale bar: 100 μm. n = 7 independent experiments. Data are presented as mean values ± SD. Unpaired two-sided Student’s t-test. h, i IHC of RANKL in the osteoarthritic joints with NGFR deficiency. Scale bar: 100 μm. Data are presented as mean values ± SD. n = 5 independent experiments. Unpaired two-sided Student’s t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 7 NGFR attenuates NF-κB activation in skeletal tissues during OA. a, b OA induces nuclear translocation of p65 in joint cells as shown by p65 IHC and quantification. Hollow arrowheads, cytoplasmic p65. Solid arrowheads, nuclear p65. Scale bar: 50 μm. Data are presented as mean values ± SD. n = 5 independent experiments. Unpaired two-sided Student’s t-test. ****p < 0.0001. c, d Nuclear translocation of p65 in the joint cells induced by OA was exacerbated by NGFR deficiency. Hollow arrowheads, cytoplasmic p65. Solid arrowheads, nuclear p65. Scale bar: 50 μm. Data are presented as mean values ± SD. n = 5 independent experiments. Unpaired two-sided Student’s t-test. ****p < 0.0001. e, g IHC of NGFR and p65 in human articular cartilage. OA 1 and OA 2 indicate different samples. f, h Quantification of IHC results of NGFR or nuclear p65. Data are presented as mean values ± SD. **p < 0.01. Scale bar: 50 μm. n = 5 independent experiments. Unpaired two-sided Student’s t-test. Source data are provided as a Source Data file.
Fig. 7 NGFR attenuates NF-κB activation in skeletal tissues during OA. a, b OA induces nuclear translocation of p65 in joint cells as shown by p65 IHC and quantification. Hollow arrowheads, cytoplasmic p65. Solid arrowheads, nuclear p65. Scale bar: 50 μm. Data are presented as mean values ± SD. n = 5 independent experiments. Unpaired two-sided Student’s t-test. ****p < 0.0001. c, d Nuclear translocation of p65 in the joint cells induced by OA was exacerbated by NGFR deficiency. Hollow arrowheads, cytoplasmic p65. Solid arrowheads, nuclear p65. Scale bar: 50 μm. Data are presented as mean values ± SD. n = 5 independent experiments. Unpaired two-sided Student’s t-test. ****p < 0.0001. e, g IHC of NGFR and p65 in human articular cartilage. OA 1 and OA 2 indicate different samples. f, h Quantification of IHC results of NGFR or nuclear p65. Data are presented as mean values ± SD. **p < 0.01. Scale bar: 50 μm. n = 5 independent experiments. Unpaired two-sided Student’s t-test. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 8 NGF-NGFR restricts the TNF/NF-κB signaling. a NGFR deletion enhanced TNF-induced phosphorylation of p65. v, empty vector; 2–8, different sgRNAs targeting Ngfr. n = 3 independent experiments. b NGF reduced TNF-induced p-p65, which required NGFR. v vehicle. T, TNF. N, NGF. T + N, TNF + NGF. Cells were treated with indicated growth factor/cytokine for 15 min. sgRNA #2 was used to generate NGFR KO. n = 3 independent experiments. c NGFR overexpression reduced p-p65 and p-IκBα in C2C12 cells treated with TNF for 24 h. R, RFP. N, hNGFR-RFP. n = 3 independent experiments. d NGFR overexpression decreased p-p65 and p-IκBα induced by TNF treatment in non-skeletal HEK293 cells. n = 3 independent experiments. e NGF treatment decreased NF-κB activation induced by TNF in HEK293 cells. n = 3 independent experiments. Source data are provided as a Source Data file.
Fig. 8 NGF-NGFR restricts the TNF/NF-κB signaling. a NGFR deletion enhanced TNF-induced phosphorylation of p65. v, empty vector; 2–8, different sgRNAs targeting Ngfr. n = 3 independent experiments. b NGF reduced TNF-induced p-p65, which required NGFR. v vehicle. T, TNF. N, NGF. T + N, TNF + NGF. Cells were treated with indicated growth factor/cytokine for 15 min. sgRNA #2 was used to generate NGFR KO. n = 3 independent experiments. c NGFR overexpression reduced p-p65 and p-IκBα in C2C12 cells treated with TNF for 24 h. R, RFP. N, hNGFR-RFP. n = 3 independent experiments. d NGFR overexpression decreased p-p65 and p-IκBα induced by TNF treatment in non-skeletal HEK293 cells. n = 3 independent experiments. e NGF treatment decreased NF-κB activation induced by TNF in HEK293 cells. n = 3 independent experiments. Source data are provided as a Source Data file.CC BY · PubMed Central

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Cited by

Sorted by citations

Metadata

Authors
Zhao, L., Lai, Y., Jiao, H., & Huang, J.
Affiliations
Rush University Medical Center (US)
Corresponding author
Huang, Jian
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-04-15
Volume
15
Issue
1
Pages
3225-3225
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-47633-6
PMC
PMC11018862
OpenAlex
W4394818993
Cited by
69
References
5
Citations by year
2026: 28 · 2025: 30 · 2024: 11
FWCI
22.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR070222, R01AR070222-04S1)
Topics
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
Keywords
nerve growth factor receptor, osteoarthritis, joint remodeling, joint repair, NF-κB activation, TNF-α, RANKL, subchondral bone, osteophytes, bone formation, bone resorption, cartilage, inflammation, skeletal progenitor cells

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