Macrophage polarization contributes to local inflammation and structural change in the multifidus muscle after intervertebral disc injury

James, Gregory; Sluka, Kathleen A.; Blomster, Linda V.; Hall, Leanne; Schmid, Annina B.; Shu, Cindy; Little, Christopher B.; Melrose, James; Hodges, Paul W.

doi:10.1007/s00586-018-5652-7

Cited by 63 publications

(67 citation statements)

References 63 publications

(137 reference statements)

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“…Although MSC treatment prevents fatty infiltration and fibrosis of the multifidus muscle after the development of an IVD lesion, it cannot prevent a muscle inflammatory response and muscle fiber transformation. These findings highlight the potential role of MSC therapy after IVD injury, but indicate other interventions may also be necessary to optimize recovery of spinal muscles such as the multifidis …”

Section: Discussionmentioning

confidence: 86%

Efficacy of administered mesenchymal stem cells in the initiation and co‐ordination of repair processes by resident disc cells in an ovine (Ovis aries) large destabilizing lesion model of experimental disc degeneration

et al. 2018

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Background Forty percent of low back pain cases are due to intervertebral disc degeneration (IVDD), with mesenchymal stem cells (MSCs) a reported treatment. We utilized an ovine IVDD model and intradiscal heterologous MSCs to determine therapeutic efficacy at different stages of IVDD. Methodology Three nonoperated control (NOC) sheep were used for MSC isolation. In 36 sheep, 6 × 20 mm annular lesions were made at three spinal levels using customized blades/scalpel handles, and IVDD was allowed to develop for 4 weeks in the Early (EA) and late Acute (LA) groups, or 12 weeks in the chronic (EST) group. Lesion IVDs received injections of 10 × 10 6 MSCs or PBS, and after 8 (EA), 22 (LA) or 14 (EST) weeks recuperation the sheep were sacrificed. Longitudinal lateral radiographs were used to determine disc heights. IVD glycosaminoglycan (GAG) and hydroxyproline contents were quantified using established methods. An Instron materials testing machine and customized jigs analyzed IVD (range of motion, neutral zone [NZ] and stiffness) in flexion/extension, lateral bending and axial rotation. qRTPCR gene profiles of key anabolic and catabolic matrix molecules were undertaken. Toluidine blue and hematoxylin and eosin stained IVD sections were histopathologically scoring by two blinded observers. Results IVDD significantly reduced disc heights. MSC treatment restored 95% to 100% of disc height, maximally improved NZ and stiffness in flexion/extension and lateral bending in the EST group, restoring GAG levels. With IVDD qRTPCR demonstrated elevated catabolic gene expression ( MMP2/3/9/13, ADAMTS4/5 ) in the PBS IVDs and expession normalization in MSC‐treated IVDs. Histopathology degeneracy scores were close to levels of NOC IVDs in MSC IVDs but IVDD developed in PBS injected IVDs. Discussion Administered MSCs produced recovery in degenerate IVDs, restored disc height, composition, biomechanical properties, down regulated MMPs and fibrosis, strongly supporting the efficacy of MSCs for disc repair.

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Section: Discussionmentioning

confidence: 86%

Efficacy of administered mesenchymal stem cells in the initiation and co‐ordination of repair processes by resident disc cells in an ovine (Ovis aries) large destabilizing lesion model of experimental disc degeneration

et al. 2018

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“…A recent study by James et al would point to a biochemical link. The authors showed, in an ovine IVD injury model, an increased proportion of pro-inflammatory M1 macrophages in paraspinal adipose tissue after disc injury, suggesting a local biochemical factors could mediate pain and inflammation in patients [55].…”

Section: Discussionmentioning

confidence: 97%

Leptin and the intervertebral disc: a biochemical link exists between obesity, intervertebral disc degeneration and low back pain—an in vitro study in a bovine model

2018

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The aim of this study was to identify the effects of leptin upon the intervertebral disc (IVD) and to determine whether these responses are potentiated within an environment of existing degeneration. Obesity is a significant risk factor for low back pain (LBP) and IVD degeneration. Adipokines, such as leptin, are novel cytokines produced primarily by adipose tissue and have been implicated in degradative and inflammatory processes. Obese individuals are known to have higher concentrations of serum leptin, and IVD cells express leptin receptors. We hypothesise that adipokines, such as leptin, mediate a biochemical link between obesity, IVD degeneration and LBP. Methods The bovine intervertebral disc was used as a model system to investigate the biochemical effects of obesity, mediated by leptin, upon the intervertebral disc. Freshly isolated cells, embedded in 3D alginate beads, were subsequently cultured under varying concentrations of leptin, alone or together with the pro-inflammatory cytokines TNF-α, IL-1β or IL-6. Responses in relation to production of nitric oxide, lactate, glycosaminoglycans and expression of anabolic and catabolic genes were analysed. Results Leptin influenced the cellular metabolism leading particularly to greater production of proteases and NO. Addition of leptin to an inflammatory environment demonstrated a marked deleterious synergistic effect with greater production of NO, MMPs and potentiation of pro-inflammatory cytokine production. Conclusions Leptin can initiate processes involved in IVD degeneration. This effect is potentiated in an environment of existing degeneration and inflammation. Hence, a biochemical mechanism may underlie the link between obesity, intervertebral disc degeneration and low back pain. Graphical abstract These slides can be retrieved under Electronic Supplementary Material.

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“…Polarization is directed by the local microenvironment and cytokine signaling. In an animal model of intervertebral disk lesions, immunofluorescence labeling of M1 and M2 macrophages indicated an increase in the proportion of M1 cells as well as an increase in TNF‐α expression, suggesting that M1 polarization plays a critical role in early stages of remodeling . In the case of knee OA, a study analyzing M1 macrophages and M2 macrophages in synovial fluid in normal versus OA knees found a higher ratio of M1/M2 in OA versus normal knees and the ratio was significantly correlated to the Kellgren‐Lawrence grade .…”

Section: Wound Healing—the Role Of the Macrophagementioning

confidence: 99%

Role of Inflammation and the Immune System in the Progression of Osteoarthritis

Woodell-May

Sommerfeld

2019

Journal Orthopaedic Research

274

172

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Understanding the molecular drivers and feedback loops of osteoarthritis (OA) may provide future therapeutic strategies to modulate the disease progression. The current paradigm of OA is evolving from a purely mechanical disease caused by cartilage wear toward a complex biological response connecting biomechanics, inflammation, and the immune system. The view of OA as a chronic wound highlights the role inflammation plays and also the body's attempts to repair an ongoing injury. Inflammatory signals, including cytokines such as interleukin-1 and tissue necrosis factor α, surface-expressed pattern recognition receptors such as toll-like receptors 2 and 4, complement factors such as C5, as well as pathogen-associated molecular patterns and damage-associated molecular patterns drive the enzymatic cascade that degrades cartilage matrix in OA. Considering the joint as an entire organ, interactions between the cells that reside in the synovium including macrophages and other immune cells, appear to drive enzymatic activity in cartilage, which, in turn, feeds signals back to the synovium that continues stimulating degradation in a feed-forward loop. This review will explore the potential roles of immune cells such as macrophages and T cells in the synovium in both stimulating and modulating the inflammatory response in OA.

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Macrophage polarization contributes to local inflammation and structural change in the multifidus muscle after intervertebral disc injury

Cited by 63 publications

References 63 publications

Efficacy of administered mesenchymal stem cells in the initiation and co‐ordination of repair processes by resident disc cells in an ovine (Ovis aries) large destabilizing lesion model of experimental disc degeneration

Efficacy of administered mesenchymal stem cells in the initiation and co‐ordination of repair processes by resident disc cells in an ovine (Ovis aries) large destabilizing lesion model of experimental disc degeneration

Leptin and the intervertebral disc: a biochemical link exists between obesity, intervertebral disc degeneration and low back pain—an in vitro study in a bovine model

Role of Inflammation and the Immune System in the Progression of Osteoarthritis

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