Kristina Möller - Academia.edu (original) (raw)

Papers by Kristina Möller

Journal of Experimental Medicine, Jun 13, 2019

Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity... more Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.

Osteoarthritis and Cartilage, 2018

assays. DMM surgeries and intra-articular injections: 12-week-old male C57Bl/6 mice underwent sur... more assays. DMM surgeries and intra-articular injections: 12-week-old male C57Bl/6 mice underwent surgery to destabilize the medial meniscus (DMM) in the right knee (n ¼ 24). Four weeks after surgery, mice received a single 3 ml intra-articular injection of saline (n ¼ 7), 8 mM NSC117079 (n ¼ 9), or 8 mM NSC45586 (n ¼ 8) in the right knee joint.

Osteoarthritis and Cartilage, 2016

PLOS ONE, Oct 5, 2012

Disability and movement-related pain are major symptoms of joint disease, motivating the developm... more Disability and movement-related pain are major symptoms of joint disease, motivating the development of methods to quantify motor behaviour in rodent joint pain models. We used observational scoring and automated methods to compare weight bearing during locomotion and during standing after single joint inflammation induced by Freund's complete adjuvant (0.12-8.0 mg/mL) or carrageenan (0.47-30 mg/mL). Automated gait analysis was based on video capture of prints generated by light projected into the long edge of the floor of a walkway, producing an illuminated image of the contact area of each paw with light intensity reflecting the contact pressure. Weight bearing was calculated as an area-integrated paw pressure, that is, the light intensity of all pixels activated during the contact phase of a paw placement. Automated static weight bearing was measured with the Incapacitance tester. Pharmacological sensitivity of weight-bearing during locomotion was tested in carrageenan-induced monoarthritis by administration of the commonly used analgesics diclofenac, ibuprofen, and naproxen, as well as oxycodone and paracetamol. Observational scoring and automated quantification yielded similar results. We found that the window between control rats and monoarthritic rats was greater during locomotion. The response was more pronounced for inflammation in the ankle as compared to the knee, suggesting a methodological advantage of using this injection site. The effects of both Freund's complete adjuvant and carrageenan were concentration related, but Freund's incomplete adjuvant was found to be as effective as lower, commonly used concentrations of the complete adjuvant. The results show that gait analysis can be an effective method to quantify behavioural effects of single joint inflammation in the rat, sensitive to analgesic treatment.

Journal of Neuroscience Methods, 2008

The CatWalk automated quantitative gait analysis technique has been validated as a method to quan... more The CatWalk automated quantitative gait analysis technique has been validated as a method to quantify behaviour in rodent models of neuropathic and arthritic pain. Its suitability for pharmacological testing of pain relief has been questioned, however, based on findings using paw soft tissue plantar inflammation as stimulus. In this study, we investigated the effectiveness of morphine and rofecoxib in reducing pain behaviour in monoarthritic rats. The CatWalk was used to assess print area, weight load and duration of stance for each paw, as well as interlimb coordination, before and 3, 5 and 24 h after injection of lambdacarrageenan into one ankle joint. The monoarthritic rat showed a reduced print area, weight load and duration of stance for the injected paw at all times tested, and a significant loss of interlimb coordination at 3 and 5 h after injection. Both morphine (3.75 and 15 mol/kg s.c.) and rofecoxib (7.5 and 30 mol/kg p.o.) reduced the effects of carrageenan. In conclusion, behavioural effects interpreted as reflecting movementrelated pain in monoarthritic rats and pharmacological treatment of the monoarthritis can objectively and efficiently be quantified in detail by the CatWalk method.

PLoS ONE, 2012

European Journal of Pharmacology, 2015

Lack of predictive power for drug effects has been a major criticism against animal pain models. ... more Lack of predictive power for drug effects has been a major criticism against animal pain models. It is therefore important to define the utility and limitations of different models. The aim of this study was to extend previous work on gait analysis as a tool to investigate pharmacological effects in monoarthritic rats, specifically to test the hypothesis that monoarthritis induced by Freund's complete adjuvant (FCA) provides a better estimate of overall analgesic efficacy of established, and novel, clinically effective and ineffective therapeutic approaches. Male rats injected intra-articularly into one ankle joint with FCA (1.0 mg/ml) were treated with the monoclonal antibody to nerve growth factor (NGF), MEDI-578, the inhibitors of tropomyosin receptor kinases A, B and C (pan-Trk) AZ6623 or AZ7092, the transient receptor potential vanilloid 1 (TRPV1) inhibitor AZD1386, or the cyclooxygenase (COX) inhibitors naproxen, ibuprofen, valdecoxib or rofecoxib. Effects on weight bearing during locomotion were tested using video capture of print images. The apparent efficacy in this model was Trk inhibitorsZanti-NGF antibody 4COX inhibitors. The TRPV1 inhibitor was ineffective. Together with previous data, the results support using gait-related parameters in the monoarthritis model. FCA as induction agent seems to provide a good overall prediction of analgesic efficacy in disorders with inflammatory joint pain.

The Journal of Experimental Medicine

Rheumatoid arthritis–associated joint pain is frequently observed independent of disease activity... more Rheumatoid arthritis–associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody–induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain–deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain–deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain–defic...

JCI Insight

Skeletal muscle weakness in patients suffering from rheumatoid arthritis (RA) adds to their impai... more Skeletal muscle weakness in patients suffering from rheumatoid arthritis (RA) adds to their impaired working abilities and reduced quality of life. However, little molecular insight is available on muscle weakness associated with RA. Oxidative stress has been implicated in the disease pathogenesis of RA. Here we show that oxidative post-translational modifications of the contractile machinery targeted to actin result in impaired actin polymerization and reduced force production. Using mass spectrometry, we identified the actin residues targeted by oxidative 3-nitrotyrosine (3-NT) or malondialdehyde adduct (MDA) modifications in weakened skeletal muscle from mice with arthritis and patients afflicted by RA. The residues were primarily located to three distinct regions positioned at matching surface areas of the skeletal muscle actin molecule from arthritis mice and RA patients. Moreover, molecular dynamic simulations revealed that these areas, here coined "hotspots", are important for the stability of the actin molecule and its capacity to generate filaments and interact with myosin. Together, these data demonstrate how oxidative modifications on actin promote muscle weakness in RA patients and provide novel leads for targeted therapeutic treatment to improve muscle function.

Journal of Neuroscience Methods

Rheumatology, 2014

Objective. Emerging evidence indicates that low-grade inflammation is part of the clinical pictur... more Objective. Emerging evidence indicates that low-grade inflammation is part of the clinical picture of OA and that there is a need to identify soluble biomarkers of ongoing inflammation in the joint from a translational aspect. The aim of this study was to compare levels of pro-inflammatory biomarkers in SF, serum and/or EDTA plasma. Methods. SF and blood from rats subjected to Freund's complete adjuvant (FCA; n = 48) or monoiodoacetate (MIA; n = 88) monoarthritis and from control rats were collected over time. SF, EDTA plasma and serum were obtained from six individuals with OA of the knee and healthy controls. Levels of IL-6, KC/ GRO, IL-8, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 3a (MIP-3a), IL-1b, TNF and L +-lactate were assessed either by immune assay or by a colorimetric method. Results. Elevated levels of biomarkers were shown in monoarthritic animals in SF compared with the control groups, although with considerably lower magnitude in the MIA groups, which also indicated a biphasic pattern. Levels of KC/GRO and MIP-3a in serum from the FCA model and IL-6 in the MIA model followed the pattern of SF. In serum samples from OA individuals, MIP-3a correlated significantly with levels in SF. Conclusion. While we found increased levels of markers in joint fluid and blood, no single systemic biochemical biomarkers that were a common denominator between the animal models and the patient material could be identified. Our data indicate that it is critical to delineate the temporal profile of multiple local and systemic factors in order to pinpoint soluble biomarkers for OA.

Neuroscience Letters, 1984

ABSTRACT

Neuroscience, 2002

öThe importance of the N-methyl-D-aspartate (NMDA) receptor in various painful conditions is well... more öThe importance of the N-methyl-D-aspartate (NMDA) receptor in various painful conditions is well established. The e¡ects of peripheral nerve lesion or joint in£ammation, as models of di¡erent pain states, on NMDA receptor-mediated currents and NMDA receptor subunit mRNA expression were therefore studied in acutely dissociated neurones from the rat spinal cord dorsal horn. In the neuronal population from control rats, all four NR2 subunits and both NR1 splice variants assayed were detected. A majority of neurones expressed mRNA for more than one NR2 subunit, and some neurones expressed all four NR2 subunits as well as both NR1 splice variants. The NR2B subunit was the most commonly expressed, while the NR2C was the rarest. Following nerve lesion, fewer neurones expressed NR2A compared to the control. The dose^response curve for glutamate-evoked NMDA receptor-mediated currents in the neurones was best described by a three-component ¢t, suggesting that three functionally distinct NMDA receptor populations are present in the dorsal horn. Minor changes in the dose^response curve after nerve lesion could not be ascribed with certainty to the lesion. Changes in other parameters of NMDA receptor-mediated currents were observed neither after nerve lesion nor after joint in£ammation. In summary, the present work demonstrates that single dorsal horn neurones express mRNA for several NMDA receptor subunits. The glutamate dose^response curves indicate that there are three major types of NMDA receptors present in dorsal horn neurones. We also report a reduced expression of NR2A following peripheral nerve lesion.

Neuropharmacology, 1992

The effects of acute doses of 8-hydroxy 2-(di-n-dipropylamino)tetralin (8-OH-DPAT) on the hypothe... more The effects of acute doses of 8-hydroxy 2-(di-n-dipropylamino)tetralin (8-OH-DPAT) on the hypothermic response, induced by a challenge dose of 8-OH-DPAT, were examined in rats. Acute doses of 8-OH-DPAT (1.0 or 0.5 mg/kg, s.c.) significantly attenuated the hypothermic response induced by 8-OH-DPAT (0.05 mg/kg, s.c.). The response to 8-OH-DPAT was almost abolished between 4 hr and 4 days and the attenuation of the response lasted for 21 days. On day 28 the response had returned to the control level. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)cyclohepten-5,10-imine [(+)MK-801], blocked this long-lasting attenuation of the 8-OH-DPAT-induced hypothermic response. Given on its own, (+)MK-801 did not reduce body temperature, at the doses used in the experiments but the drug did block the acute effects of 8-OH-DPAT, at the same doses which blocked the attenuation of the hypothermic response. The present data suggest that stimulation of glutamate NMDA receptors may underlie the long-lasting effect of acute injections of 8-OH-DPAT.

Neuropharmacology, 1990

The effects of repeated treatment of rats with I-hydroxy-Z(di-n-propylamino)tetralin (g-OH-DPAT),... more The effects of repeated treatment of rats with I-hydroxy-Z(di-n-propylamino)tetralin (g-OH-DPAT), 1 .O mg/kg, subcutaneously, twice daily for 7 days, on the stimulation of post-and presynaptic 5-HT,, receptors were examined. The postsynaptic responses, hypothermia and inhibition of the cage-leaving response, evoked by 0.05 mg/kg 8-OH-DPAT, were measured 48 hr after the final injection. Another postsynaptic response, the 5-HT syndrome (flat body posture and forepaw treading) was observed after the third injection of 8-OH-DPAT (1.0 mg/kg s.c.). One presynaptic response examined was the I-OH-DPAT-induced decrease in the concentration of 5-hydroxyindoleacetic acid (5-HIAA), that indicates a decrease in turnover of 5-HT, due to stimulation of 5-HT receptors on the cell bodies and measured as the ratio of 5-HIAA to S-HT in the hippocampus, hypothalamus and medulla oblongata. Another presynaptic response was the 8-OH-DPAT-induced decrease in the accumulation of 5-hydroxytryptophan (5-HTP) in the hippocampus and hypothalamus, after inhibition of L-aromatic amino acid decarboxylase by 3-hydroxybenzylhydrazine (NSD 1015), that is due to stimulation of autoreceptors on the 5-HT cell bodies. The kinetic properties of 5-HT,, receptors in the cerebra1 cortex and hippocampus, hippocampus alone, hypothalamus and medulla oblongata were determined with.[3H]8-OH-DPAT. It was found that the postsynaptic effects were markedly attenuated after the treatment, the hypothermic effect already after a single dose. The strength of the 5-HT syndrome was almost abolished, when measured one day after the third injection, and still markedly decreased 1 but not 2 weeks after this injection. In contrast to these changes, no attenuation of the decrease in the turnover of 5-HT or the accumulation of 5-HTP was found in any of the regions examined. The kinetic parameters of the 5-HT,, receptors (&,, and &) were also unchanged in all the regions analyzed. These findings, which are contradictory to some previous observations, indicate that pre-and postsynaptic 5-HT,, receptor responses are mediated by different signal systems and that some of them, possibly G, proteins coupled to adenylate cyclase, may be quite sensitive to repeated stimulation.

Journal of Pharmacological and Toxicological Methods, 1994

This study compares two methods for evaluating pain-related behavior in an animal model with carr... more This study compares two methods for evaluating pain-related behavior in an animal model with carrageenan-induced monoarthritis. Rats injected with lambda-carrageenan into the right tibio-tarsal joint were videofilmed at various times after injection and later scored regarding their stance. Immediately after each videorecording session the animals were tested in a box constructed to register the weight load exerted by the hindpaws by means of force plates inserted in the floor. Following carrageenan injection (300 micrograms in 50 microL) the load on the injected paw fell from a control value of 39.3% +/- 0.4% of the body weight (mean +/- SEM, n = 6) to a minimum of 5.1% +/- 1.8% at 6 hr and then slowly increased to approach control levels at 72 hr. The weight load on the contralateral paw increased from a control value of 38.9% +/- 0.6% to 52.4% +/- 1.4% at 6 hr, whereafter it gradually decreased. The video-based stance scores also showed a maximal impairment at 4-6 hr, with a gradual return towards control values at 72 hr. However, the results based on the force plate measurements were less variable and more graded. Morphine inhibited the carrageenan-induced effect in a dose-dependent manner in both paradigms. In conclusion, the present results indicate that measurement of weight bearing as described in the present paper is a practical, useful, and objective method to assess the degree of arthritic pain in the rat.

European Journal of Pharmacology, 1984

The ergolene derivative MPME (PTR 17402; (5R,8R)-8-(4-p-methoxyphenyl)-1-piperazynylmethyl-6- met... more The ergolene derivative MPME (PTR 17402; (5R,8R)-8-(4-p-methoxyphenyl)-1-piperazynylmethyl-6- methylergolene], a dopamine (DA) receptor agonist acting mainly at DA D-1 receptors linked to dotted types of forebrain DA nerve terminals, induces a characteristic behavioural syndrome consisting of increased locomotion, head-bobbing and sniffing activity without oral stereotypies or increased rearing. Haloperidol and cis-flupenthixol, nonselective DA receptor antagonists, but not selective D-2 receptor antagonists such as remoxipride and sulpiride, could significantly counteract the locomotion and head-bobbing behaviour induced by MPME. In contrast, the sniffing behaviour induced by MPME was only marginally affected by haloperidol and cis-flupenthixol pretreatment. These results suggest that activation of D-1 receptors in the forebrain mainly linked to the dotted types of DA nerve terminals in the striatum, and in the limbic forebrain, can result in behavioural effects which differ from those caused by stimulation of D-2 receptors located mainly within the diffuse types of DA nerve terminal systems.