Microarray analysis of bone marrow lesions in osteoarthritis demonstrates upregulation of genes implicated in osteochondral turnover, neurogenesis and inflammation

Kuttapitiya, Anasuya; Assi, L.; Laing, Ken; Hing, Caroline B.; Mitchell, Philip; Whitley, Guy; Harrison, Abiola; Howe, Franklyn A.; Ejindu, Vivian; Heron, Christine; Sofat, Nidhi

doi:10.1136/annrheumdis-2017-211396

Cited by 102 publications

(122 citation statements)

References 44 publications

(43 reference statements)

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“…STMN2 also plays a role in the control of neuronal differentiation. Moreover, STMN2 is expressed during osteogenesis and it was previously shown to be highly upregulated in OA bone marrow lesions as compared to control bone samples [8,31]. In addition, we found other neural markers to be upregulated in lesioned compared to preserved OA subchondral bone, such as NGF and THBS3 (Supplementary Table 3).…”

Section: Differential Expression Analysis Of the Gene Expression Levesupporting

confidence: 53%

“…In addition, studies have shown an association between the bone mineral density and development of OA, which suggest that the subchondral bone is involved in the early stages of OA [13,15]. This was also suggested by studies regarding subchondral bone marrow lesions, showing these to be very early markers of OA [8,16].…”

Section: Introductionmentioning

confidence: 82%

“…To date, major efforts have been made trying to characterize pathophysiological processes of OA in articular cartilage. However, only few studies focus on OA pathophysiological processes in the underlying bone [7,8].…”

Section: Introductionmentioning

confidence: 99%

“…Chou et al [7] performed whole genome expression profiling of non-OA and OA subchondral bone using microarray analysis, which led to identification of genes involved in pathways such as lipid metabolism and mineral metabolism. Kuttapitiya et al [8] used microarray analysis to identify genes involved in bone remodeling, pain sensitization, and matrix turnover being differentially expressed between OA bone marrow lesion tissue and controls. Nevertheless, these studies were performed using microarray and did solely include knee samples.…”

Section: Introductionmentioning

confidence: 99%

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RNA sequencing reveals interacting key determinants of osteoarthritis acting in subchondral bone and articular cartilage

Tuerlings

Hoolwerff

Houtman

et al. 2020

Preprint

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Objective: The aim of this study was to identify key determinants of the interactive osteoarthritis (OA) pathophysiological processes of subchondral bone and cartilage. Methods:We performed RNA sequencing on macroscopically preserved and lesioned OA subchondral bone of patients that underwent joint replacement surgery due to OA (N=24 pairs; 6 hips, 18 knees, RAAK-study). Unsupervised hierarchical clustering and differential expression analyses were performed. Results were combined with previously identified, differentially expressed genes in cartilage (partly overlapping samples) as well as with recently identified OA risk genes . Results:We identified 1569 genes significantly differentially expressed between lesioned and preserved subchondral bone, including CNTNAP2 (FC=2.4, FDR=3.36x10 -5 ) and STMN2 (FC=9.6, FDR=3.36x10 -3 ). Among the identified genes, 305 were also differentially expressed and with same direction of effects in cartilage, including IL11 and CHADL, recently acknowledged OA susceptibility genes. Upon differential expression analysis stratifying for joint site, we identified 509 genes exclusively differentially expressed in subchondral bone of the knee, such as KLF11 and WNT4. These exclusive knee genes were enriched for involvement in epigenetic processes, characterized by for instance HIST1H3J and HIST1H3H. Conclusion:To our knowledge, we are the first to report on differential gene expression patterns of paired OA subchondral bone tissue using RNA sequencing. Among the most consistently differentially expressed genes with OA pathophysiology in both bone and cartilage were IL11 and CHADL. As these genes were recently also identified as robust OA risk genes they classify as attractive druggable targets acting on two OA disease relevant tissues.

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Section: Differential Expression Analysis Of the Gene Expression Levesupporting

confidence: 53%

Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

RNA sequencing reveals interacting key determinants of osteoarthritis acting in subchondral bone and articular cartilage

Tuerlings

Hoolwerff

Houtman

et al. 2020

Preprint

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“…So-called bone marrow lesions (BML) are associated with OA and its pain (Kuttapitiya et al, 2017). In a collaboration with Dr N. Sofat, St Georges Hospital Medical School London, we are studying some of this material.…”

Section: Human Bonementioning

confidence: 99%

Evaluation of laser ablation microtomy for correlative microscopy of hard tissues

Boyde

2018

Journal of Microscopy

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Laser ablation machining or microtomy (LAM) is a relatively new approach to producing slide mounted sections of translucent materials. We evaluated the method with a variety of problems from the bone, joint and dental tissues fields where we require thin undecalcified and undistorted sections for correlative light microscopy (LM) and backscattered electron scanning electron microscopy (BSE SEM). All samples were embedded in poly-methylmethacrlate (PMMA) and flat block surfaces had been previously studied by BSE-SEM and confocal scanning light microscopy (CSLM). Most were also studied by X-yay microtomography (XMT). The block surface is stuck to a glass slide with cyanoacrylate adhesive. Setting the section thickness and levelling uses inbuilt optical coherence tomographic imaging. Tight focusing of near-infrared laser radiation in the sectioning plane gives extreme intensities causing photodisruption of material at the focal point. The laser beam is moved by a fast scanner to write a cutting line, which is simultaneously moved by an XY positioning unit to create a sectioning plane. The block is thereby released from the slide, leaving the section stuck to the slide. Light, wet polishing on the finest grade (4000 grit) silicon carbide polishing paper is used to remove a 1-2 μm thick damaged layer at the surface of the section. Sections produced by laser cutting are fine in quality and superior to those produced by mechanical cutting and can be thinner than the 'voxel' in most laboratory X-ray microtomography systems. The present extensive pilot studies have shown that it works to produce samples which we can study by both light and electron microscopy.

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Effect of Intravenous Zoledronic Acid on Tibiofemoral Cartilage Volume Among Patients With Knee Osteoarthritis With Bone Marrow Lesions

Cai

Aitken

Laslett

et al. 2020

JAMA

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IMPORTANCE A proof-of-principle study suggested that intravenous zoledronic acid may reduce knee pain and the size of bone marrow lesions in people with knee osteoarthritis, but data from large trials are lacking.OBJECTIVE To determine the effects of intravenous zoledronic acid on knee cartilage volume loss in patients with symptomatic knee osteoarthritis and bone marrow lesions. DESIGN, SETTING, AND PARTICIPANTSA 24-month multicenter, double-blind placebo-controlled randomized clinical trial conducted at 4 sites in Australia (1 research center and 3 hospitals). Adults aged 50 years or older with symptomatic knee osteoarthritis and subchondral bone marrow lesions detected by magnetic resonance imaging (MRI) were enrolled from November 2013 through September 2015. The final date of follow-up was October 9, 2017.INTERVENTIONS Intravenous infusion with either 5 mg of zoledronic acid in a 100-mL saline solution (n = 113) or a placebo saline solution (n = 110) at baseline and 12 months. MAIN OUTCOMES AND MEASURESThe primary outcome was absolute change in tibiofemoral cartilage volume assessed using MRI over 24 months (the minimum clinically important difference [MCID] has not been established). Three prespecified secondary outcomes were change in knee pain assessed by a visual analog scale (0 [no pain] to 100 [unbearable pain]; MCID, 15) and the Western Ontario and McMaster Universities Osteoarthritis Index (0 [no pain] to 500 [unbearable pain]; MCID, 75) over 3, 6, 12, 18, and 24 months and change in bone marrow lesion size over 6 and 24 months (the MCID has not been established). RESULTSOf 223 participants enrolled (mean age, 62.0 years [SD, 8.0 years]; 52% were female), 190 (85%) completed the trial. Change in tibiofemoral cartilage volume was not significantly different between the zoledronic acid group and the placebo group over 24 months (−878 mm 3 vs −919 mm 3 ; between-group difference, 41 mm 3 [95% CI, −79 to 161 mm 3 ]; P = .50). No significant between-group differences were found for any of the prespecified secondary outcomes, including changes in knee pain assessed by a visual analog scale (−11.5 in the zoledronic acid group vs −16.8 in the placebo group; between-group difference, 5.2 [95% CI, −2.3 to 12.8]; P = .17), changes in knee pain assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (−37.5 vs −58.0, respectively; between-group difference, 20.5 [95% CI, −11.2 to 52.2]; P = .21), and changes in bone marrow lesion size (−33 mm 2 vs −6 mm 2 ; between-group difference, −27 mm 2 [95% CI, −127 to 73 mm 2 ]; P = .60) over 24 months. Adverse events were more common with zoledronic acid than with placebo (96% vs 83%, respectively) and consisted mainly of acute reactions (defined as symptoms within 3 days of administration of infusion; 87% vs 56%).CONCLUSIONS AND RELEVANCE Among patients with symptomatic knee osteoarthritis and bone marrow lesions, yearly zoledronic acid infusions, compared with placebo, did not significantly reduce cartilage volume loss over 24 months. These finding...

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Microarray analysis of bone marrow lesions in osteoarthritis demonstrates upregulation of genes implicated in osteochondral turnover, neurogenesis and inflammation

Cited by 102 publications

References 44 publications

RNA sequencing reveals interacting key determinants of osteoarthritis acting in subchondral bone and articular cartilage

RNA sequencing reveals interacting key determinants of osteoarthritis acting in subchondral bone and articular cartilage

Evaluation of laser ablation microtomy for correlative microscopy of hard tissues

Effect of Intravenous Zoledronic Acid on Tibiofemoral Cartilage Volume Among Patients With Knee Osteoarthritis With Bone Marrow Lesions

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