Abstract
Chronic low back pain is a highly prevalent health condition intricately linked to intervertebral disc degeneration. One of the prominent features of disc degeneration that is commonly observed with aging is dystrophic calcification. ATP-binding cassette sub-family C member 6 (ABCC6), a presumed ATP efflux transporter, is a key regulator of systemic levels of the mineralization inhibitor pyrophosphate (PPi). Mutations in ABCC6 result in pseudoxanthoma elasticum (PXE), a progressive human metabolic disorder characterized by mineralization of the skin and elastic tissues. The implications of ABCC6 loss-of-function on pathological mineralization of structures in the spine, however, are unknown. Using the Abcc6 −/− mouse model of PXE, we investigated age-dependent changes in the vertebral bone and intervertebral disc. Abcc6 −/− mice exhibited diminished trabecular bone quality parameters at 7 months, which remained significantly lower than the wild-type mice at 18 months of age. Abcc6 −/− vertebrae showed increased TRAP staining along with decreased TNAP staining, suggesting an enhanced bone resorption as well as decreased bone formation. Surprisingly, however, loss of ABCC6 resulted only in a mild, aging disc phenotype without evidence of dystrophic mineralization. Finally, we tested the utility of oral K3Citrate to treat the vertebral phenotype since it is shown to regulate hydroxyapatite mechanical behavior. The treatment resulted in inhibition of the osteoclastic response and an early improvement in mechanical properties of the bone underscoring the promise of potassium citrate as a therapeutic agent. Our data suggest that although ectopic mineralization is tightly regulated in the disc, loss of ABCC6 compromises vertebral bone quality and dysregulates osteoblast-osteoclast coupling.
Highlights
The ATP-binding cassette sub-family C member 6 (ABCC6) protein is a mediator of cellular ATP release (Jansen et al, 2013; Jansen et al, 2014) into the blood from hepatocytes where it is primarily expressed
pseudoxanthoma elasticum (PXE) is an extensively studied mineralization disorder and use of mouse models recapitulating PXE has provided extensive knowledge about ABCC6 function in maintaining the health of elastin-rich tissues that are prone to ectopic mineralization
While dystrophic calcification is one of the known phenotypes of intervertebral disc degeneration, it is unknown whether PXE affects mineralization pathways in the disc and ABCC6 is not expressed in the spine, its systemic effects on the spine have not been studied in detail
Summary
The ABCC6 protein is a mediator of cellular ATP release (Jansen et al, 2013; Jansen et al, 2014) into the blood from hepatocytes where it is primarily expressed. Absence of ABCC6 causes pseudoxanthoma elasticum (PXE), an autosomal recessive metabolic disorder characterized by ectopic mineralization in elastin-rich tissues such as the eyes, blood vessel walls, and the skin (Borst et al, 2019). While ABCC6 is highly expressed in the liver and kidneys, it is minimally expressed, or absent, in elastin-rich tissues affected by PXE (Klement et al, 2005). The PPi produced in the liver is distributed to peripheral organs through blood, with ABCC6 contributing about 60–70% of plasma PPi (Jansen et al, 2013; Jansen et al, 2014) underscoring the metabolic nature of PXE
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