Drug-induced changes to the vertebral endplate vasculature affect transport into the intervertebral disc in vivo

Gullbrand, Sarah E.; Peterson, Joshua; Mastropolo, Rosemarie; Lawrence, James P.; Lopes, Luciana B.; Lotz, Jeffrey C.; Ledet, Eric H.

doi:10.1002/jor.22716

Cited by 20 publications

(26 citation statements)

References 40 publications

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“…These changes are similar to those found in subchondral bone of OA patients and animal models7. TGFβ released from latent extracellular matrix mobilizes and recruits MSCs232425. MSCs are thought to localize with vasculature26.…”

Section: Discussionsupporting

confidence: 67%

Excessive Activation of TGFβ by Spinal Instability Causes Vertebral Endplate Sclerosis

Bian

Jain

et al. 2016

Sci Rep

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Narrowed intervertebral disc (IVD) space is a characteristic of IVD degeneration. EP sclerosis is associated with IVD, however the pathogenesis of EP hypertrophy is poorly understood. Here, we employed two spine instability mouse models to investigate temporal and spatial EP changes associated with IVD volume, considering them as a functional unit. We found that aberrant mechanical loading leads to accelerated ossification and hypertrophy of EP, decreased IVD volume and increased activation of TGFβ. Overexpression of active TGFβ in CED mice showed a similar phenotype of spine instability model. Administration of TGFβ Receptor I inhibitor attenuates pathologic changes of EP and prevents IVD narrowing. The aberrant activation of TGFβ resulting in EPs hypertrophy-induced IVD space narrowing provides a pharmacologic target that could have therapeutic potential to delay DDD.Degenerative disc disease (DDD) is one of the most common musculoskeletal disorders that is associated with disability and absenteeism from work. Degeneration has been detected as early as teenage years and severe degeneration is found in 60% of 70-year olds 1,2 . DDD typically presents with back pain and imposes an enormous socio-economic burden, over $100 billion annually in the US alone. This cost exceeds the combined costs of stroke, respiratory infection, diabetes, coronary artery disease and rheumatoid disease 1,2 . Several factors have been implicated to cause DDD such as aging, genetic predisposition, toxic factors, metabolic disorders, low-grade infection, neurogenic inflammation and mechanical factors 3 . However, the pathogenesis of DDD under mechanical loading environment is not well known.Intervertebral disc (IVD) is composed of three parts: gel-like nucleus pulposus (NP) in the central compartment surrounded by an annulus fibrosis (AF) ring, and both cranial and caudal cartilage endplates (EPs) that attach the IVD inner ring to the adjacent vertebrae. EPs transmit mechanical loads produced by body weight and muscle activity between the bony vertebrae and soft tissue 4 . Moreover, EPs serve as a selective permeability barrier, allowing passage of small solutes, such as nutrient substances but impeding transport of larger solutes such as inflammatory factors 5 . Sclerosis of EPs change the mechanical property and impair diffusion and nutrient supply, thus accelerating IVD degeneration 5 . However, the originating mechanism of EP pathology is still not clearly understood.EPs undergo calcification and ossification and become sclerotic with aging 6 . We have previously found that excess activation of TGFβ causes sclerosis and angiogenesis of subchondral bone in the knee joint, which alters loading distribution on articular cartilage and is key in the pathogenesis of osteoarthritis (OA) 7,8 . Upregulation of TGFβ has been observed in calcified hypertrophic EPs of degenerative IVD 9 . Whether TGFβ is involved in EP sclerotic changes is unknown.In this study, we investigated temporal and spatial EP changes resulting from mechanical stress by...

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Section: Discussionsupporting

confidence: 67%

Excessive Activation of TGFβ by Spinal Instability Causes Vertebral Endplate Sclerosis

Bian

Jain

et al. 2016

Sci Rep

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“…A recently published study reported angiogenesis in the SB regions of degenerating discs [24]. In another study, researchers induced angiogenesis in the SB of rabbits using nimodipine and investigated changes in contrast enhancement in the NP [25]. Interestingly, their study showed that the relationship between the SB microvasculature and solute transport into the NP was not straightforward.…”

Section: Discussionmentioning

confidence: 99%

Changes in perfusion and diffusion in the endplate regions of degenerating intervertebral discs: a DCE-MRI study

et al. 2015

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Purpose Dynamic Contrast Enhanced MRI (DCE-MRI) was used to investigate the associations between intervertebral disc degeneration and changes in perfusion and diffusion in the disc endplates. Methods 56 participants underwent MRI scans. Changes in DCE-MRI signal enhancement in the endplate regions were analyzed. Also, a group template was generated for the endplates and enhancement maps were registered to this template for group analysis. Results DCE-MRI enhancement changed significantly in cranial endplates with increased degeneration. A similar trend was observed for caudal endplates, but it was not significant. Group-averaged enhancement maps revealed major changes in spatial distribution of endplate perfusion and diffusion with increasing disc degeneration especially in peripheral endplate regions. Conclusions Increased enhancement in the endplate regions of degenerating discs might be an indication of ongoing damage in these tissues. Therefore, DCE-MRI could aid in understanding the pathophysiology of disc degeneration. Moreover, it could be used in the planning of novel treatments such as stem cell therapy.

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“…It is possible that a certain amount of cell death following in vivo implantation will be acceptable, so long as the formed matrix is retained and the remaining cell population is sufficient to maintain long‐term homeostasis of the tissue overall. Strategies to enhance nutrient transport into engineered discs in vivo, such as enhancement of the vertebral endplate vasculature or stimulation of convective transport via dynamic loading, may ultimately be necessary for the success of engineered constructs in vivo …”

Section: Challenges For In Vivo Translation Of An Engineered Discmentioning

confidence: 99%

“…12 The permeability, composition, and vascularity of the EP significantly impact diffusion of small molecules into the disc. 13,14 In addition to this challenging nutritional environment, disc cells are also subject to large magnitudes of loading in both compression and torsion during spinal motion associated with normal daily activity. Loads on the intervertebral disc can exceed up to 5 times body weight, depending on nature of the activity.…”

Section: Intervertebral Disc Structure and Mechanical Functionmentioning

confidence: 99%

“…Strategies to enhance nutrient transport into engineered discs in vivo, such as enhancement of the vertebral endplate vasculature or stimulation of convective transport via dynamic loading, may ultimately be necessary for the success of engineered constructs in vivo. 14,80 As another approach, acclimation of engineered discs to the harsh low glucose and oxygen environment of the native disc may also improve in vivo performance, and could potentially be achieved via preculture methods to reduce construct metabolic activity prior to implantation. This could include mild hypothermia, serum starvation, hypoxic culture or other strategies that are applied for a period of time prior to implantation.…”

Section: Scale Up Of Tissue-engineered Discs To Clinically Relevantmentioning

confidence: 99%

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Promise, progress, and problems in whole disc tissue engineering

Gullbrand

Smith

et al. 2018

JOR Spine

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Intervertebral disc degeneration is frequently implicated as a cause of back and neck pain, which are pervasive musculoskeletal complaints in modern society. For the treatment of end stage disc degeneration, replacement of the disc with a viable, tissue-engineered construct that mimics native disc structure and function is a promising alternative to fusion or mechanical arthroplasty techniques. Substantial progress has been made in the field of whole disc tissue engineering over the past decade, with a variety of innovative designs characterized both in vitro and in vivo in animal models. However, significant barriers to clinical translation remain, including construct size, cell source, culture technique, and the identification of appropriate animal models for preclinical evaluation. Here we review the clinical need for disc tissue engineering, the current state of the field, and the outstanding challenges that will need to be addressed by future work in this area. K E Y W O R D Sanimal models, biomaterials, biomechanics, disc degeneration, mesenchymal stem cells | INTRODUCTIONBack and neck pain place a significant social and economic burden on modern society, affecting nearly 1 in 2 individuals annually. In the United States alone, these conditions are associated with an estimated $194 billion in yearly medical costs and lost wages. Back pain is commonly associated with degenerative disc disease, a progressive condition with complex underlying etiology, during which component tissues undergo an array of cellular and structural changes that ultimately compromises biomechanical function.Although the pathological manifestations of disc degeneration are well characterized, the underlying causes and the origins of discogenic pain are still not well understood, impeding the development of effective therapies. Current treatments for disc degeneration do not restore native disc structure and function, and thus exhibit limited long-term efficacy. Tissue engineering offers the promise of generating de novo, living structures that recapitulate the form, function, and biology of healthy host tissues with the potential to treat a variety musculoskeletal disorders, including disc degeneration. Here, we review recent progress in the field of whole disc tissue engineering as well as the barriers that will need to be addressed for the successful clinical translation of engineered discs. | INTERVERTEBRAL DISC STRUCTURE AND MECHANICAL FUNCTIONThe intervertebral discs of the spine are composite structures composed of the central nucleus pulposus (NP), the peripheral annulus fibrosus (AF), and the superior and inferior cartilaginous end plates.The extracellular matrix (ECM) of the NP is composed primarily of proteoglycans and type II collagen; the high proteoglycan content of | INTERVERTEBRAL DISC DEGENERATION AND TREATMENTDegeneration of the intervertebral discs may occur with aging or following injury. While the exact pathophysiology of disc degeneration remains unclear, it is known to involve a progressive cascade of cellular,...

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Drug-induced changes to the vertebral endplate vasculature affect transport into the intervertebral disc in vivo

Cited by 20 publications

References 40 publications

Excessive Activation of TGFβ by Spinal Instability Causes Vertebral Endplate Sclerosis

Excessive Activation of TGFβ by Spinal Instability Causes Vertebral Endplate Sclerosis

Changes in perfusion and diffusion in the endplate regions of degenerating intervertebral discs: a DCE-MRI study

Promise, progress, and problems in whole disc tissue engineering

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