Therapeutic effects of an anti-ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis

Miller, Rachel E.; Tran, Phuong B.; Ishihara, Shingo; Larkin, J.; Malfait, Anne‐Marie

doi:10.1016/j.joca.2015.09.005

Cited by 64 publications

(83 citation statements)

References 33 publications

(51 reference statements)

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“…As previously reported, we confirmed that the withdrawal threshold was unchanged in naïve mice, while DMM mice developed mechanical allodynia by week 4, which was maintained for the 16-week follow-up period after surgery [6, 38] (data not shown). Four, 8, and 16 weeks after DMM or 8 weeks after sham surgery, we assessed the L4 level of the dorsal horn for Iba1 immunoreactivity, a marker for microglia, and assessed the number of Iba1-ir cells that had an activated morphology (Fig.…”

Section: Resultssupporting

confidence: 90%

“…In contrast, joint damage after DMM surgery progresses very slowly: during the first 8 weeks, cartilage degeneration and osteophyte formation are mild to moderate, while joint damage accelerates between weeks 8 and 16 [38, 49]. Concomitantly with progressive joint damage, DMM mice develop progressive mechanical allodynia [21, 23], which appears 4 weeks after surgery and is maintained for 16 weeks, whereas sham surgery results in a short-lived mechanical allodynia at 4 weeks [22].…”

Section: Discussionmentioning

confidence: 99%

“…Scoring was performed by an evaluator who was blinded to the experimental groups. Cartilage degeneration and osteophytes were scored using a previously described system [38]. Briefly, cartilage degeneration was scored on the medial femoral condyle and tibial plateau with 0 representing no damage and 30 the maximal score.…”

Section: Methodsmentioning

confidence: 99%

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Spinal microglial activation in a murine surgical model of knee osteoarthritis

Tran

Miller

Ishihara

et al. 2017

Osteoarthritis and Cartilage

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Objective Microgliosis, the activation of microglial cells, is thought to contribute to synaptic transmission in the dorsal horn and thereby promote chronic pain. The primary aim of this study was to document the temporal profile of dorsal horn microgliosis after destabilization of the medial meniscus (DMM) in wild type (WT) and Adamts5 null mice. Since neuronal fractalkine (CX3CL1) contributes to microgliosis, we assessed its release from dorsal root ganglia (DRG) cultures after DMM. Design DMM or sham surgery was performed in the right knee of 10-week old male WT, CX3CR1-GFP, or Adamts5 null C57BL/6 mice. Hindpaw mechanical allodynia was monitored using von Frey fibers. L4 dorsal horn microgliosis was assessed 4, 8 and 16 weeks after surgery, based on the morphology of Iba1-immunoreactive microglia. DRG cells (L3-L5) were cultured and supernatants collected for fractalkine ELISA. Results In WT mice, numbers of activated microglia were increased 8 and 16 weeks, but not 4 weeks, after DMM but not sham surgery. DRG cultures showed increased basal fractalkine release at 8 and 16 weeks. Adamts5 null mice did not develop mechanical allodynia up to 16 weeks after DMM. Accordingly, DRG cultures from these mice did not exhibit increased fractalkine release and dorsal horn microgliosis did not occur. Conclusion DMM surgery leads to late stage dorsal horn microgliosis. The temporal correlation with DRG fractalkine release suggests it may contribute to microgliosis. Reduced microgliosis in Adamts5 null mice, which are protected from joint damage and associated mechanical allodynia after DMM, suggests that microgliosis is associated with joint damage and accompanying persistent pain.

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Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Spinal microglial activation in a murine surgical model of knee osteoarthritis

Tran

Miller

Ishihara

et al. 2017

Osteoarthritis and Cartilage

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“…12 The DMM model is a well-defined joint instability-induced OA model, and has been widely used to study the roles of various molecular signaling pathways in PTOA. 13–17 After DMM, mild-to-moderate histological OA signs usually start at 4 weeks, and become significant at 8–12 weeks. 12 To evaluate the chronological changes in the nanomechanical properties of cartilage, we performed atomic force microscopy (AFM)-based nanoindentation on femoral condyle cartilage surfaces from 3 days to 12 weeks after DMM, and compared the results against joint morphological changes detected by histology and μCT.…”

Section: Introductionmentioning

confidence: 99%

Nanoindentation modulus of murine cartilage: a sensitive indicator of the initiation and progression of post-traumatic osteoarthritis

Doyran

Tong

et al. 2017

Osteoarthritis and Cartilage

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Objective This study aims to demonstrate that cartilage nanoindentation modulus is a highly sensitive indicator of the onset and spatiotemporal progression of post-traumatic osteoarthritis (PTOA) in murine models. Design Destabilization of medial meniscus (DMM) surgery was performed on the right knees of 12-week old male, wild-type C57BL/6 mice, with Sham control on contralateral left knees. Atomic force microscopy (AFM)-based nanoindentation was applied to quantify the nanoindentation modulus, Eind, of femoral condyle cartilage at 3 days to 12 weeks after surgery. The modulus changes were compared against the timeline of histological OA signs. Meanwhile, at 8 weeks after surgery, changes in meniscus, synovium and subchondral bone were evaluated to reveal the spatial progression of PTOA. Results The modulus of medial condyle cartilage was significantly reduced at 1 week after DMM, preceding the histological OA signs, which only become detectable at 4 – 8 weeks after. This reduction is likely due to concomitantly elevated proteolytic activities, as blocking enzymatic activities in mice can attenuate this modulus reduction. In later OA, lateral condyle cartilage and medial meniscus also started to be weakened, illustrating the whole-organ nature of PTOA. Conclusions This study underscores the high sensitivity of nanoindentation in examining the initiation, attenuation and progression of PTOA in murine model. Meanwhile, modulus changes highlight concomitant changes in lateral cartilage and meniscus during the advancement of OA.

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“…By 2–4 weeks after DMM surgery, mild cartilage lesions, subchondral bone sclerosis, and osteophytes are evident (15, 19–21), while synovitis has recently been reported to peak during this time as well (16). As the disease progresses, cartilage lesions worsen, osteophytes mature, and synovitis resolves, but not completely (16, 22).…”

Section: Introductionmentioning

confidence: 99%

Chemogenetic Inhibition of Pain Neurons in a Mouse Model of Osteoarthritis

Miller

Ishihara

Bhattacharyya

et al. 2017

Arthritis & Rheumatology

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Objective The purpose of this study was to determine the ability of drugs that activate inhibitory G-protein coupled receptors (GPCRs) expressed in peripheral NaV1.8-positive sensory neurons to control osteoarthritis associated pain. Therefore, we used Designer Receptors Exclusively Activated by a Designer Drug (DREADD) technology, which utilizes engineered GPCRs to activate or inhibit neurons upon binding the synthetic ligand, clozapine-N-oxide. Methods NaV1.8-Pdi C57BL/6 mice were created to express the inhibitory DREADD receptor, Pdi, in NaV1.8-expressing sensory neurons. Destabilization of the medial meniscus (DMM) was performed in 10-week old male mice. Four, 8, 12 or 16 weeks after surgery, knee hyperalgesia or hindpaw mechanical allodynia were tested. Subsequently, clozapine-N-oxide or vehicle was administered and the effect on behaviors was measured by a blinded observer. Morphine was used as a control. Results Immunohistochemistry and electrophysiology confirmed functional expression of the Pdi receptor by NaV1.8-positive sensory neurons. Acute inhibition of NaV1.8-expressing neurons in mice treated with clozapine-N-oxide reduced knee hyperalgesia 4 weeks after DMM and mechanical allodynia 8 weeks after DMM. Inhibition had no effect on behaviors 12 and 16 weeks after DMM. Morphine, a drug that activates GPCRs in the peripheral and central nervous systems, was still effective in the later stage. Conclusions Chemogenetic inhibition of NaV1.8-expressing neurons blocks knee hyperalgesia and mechanical allodynia in early experimental osteoarthritis, but is no longer efficacious in the later stages. These data indicate that activation of inhibitory GPCRs located solely outside the central nervous system may be ineffective in treating chronic osteoarthritis pain.

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Therapeutic effects of an anti-ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis

Cited by 64 publications

References 33 publications

Spinal microglial activation in a murine surgical model of knee osteoarthritis

Spinal microglial activation in a murine surgical model of knee osteoarthritis

Nanoindentation modulus of murine cartilage: a sensitive indicator of the initiation and progression of post-traumatic osteoarthritis

Chemogenetic Inhibition of Pain Neurons in a Mouse Model of Osteoarthritis

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