Abstract
Back pain is a common condition with a high social impact and represents a global health burden. Intervertebral disc disease (IVDD) is one of the major causes of back pain; no therapeutics are currently available to reverse this disease. The impact of bone mineral density (BMD) on IVDD has been controversial, with some studies suggesting osteoporosis as causative for IVDD and others suggesting it as protective for IVDD. Functional studies to evaluate the influence of genetic components of BMD in IVDD could highlight opportunities for drug development and repurposing. By taking a holistic 3D approach, we established an aging zebrafish model for spontaneous IVDD. Increased BMD in aging, detected by automated computational analysis, is caused by bone deformities at the endplates. However, aged zebrafish spines showed changes in bone morphology, microstructure, mineral heterogeneity, and increased fragility that resembled osteoporosis. Elements of the discs recapitulated IVDD symptoms found in humans: the intervertebral ligament (equivalent to the annulus fibrosus) showed disorganized collagen fibers and herniation, while the disc center (nucleus pulposus equivalent) showed dehydration and cellular abnormalities. We manipulated BMD in young zebrafish by mutating sp7 and cathepsin K, leading to low and high BMD, respectively. Remarkably, we detected IVDD in both groups, demonstrating that low BMD does not protect against IVDD, and we found a strong correlation between high BMD and IVDD. Deep learning was applied to high-resolution synchrotron µCT image data to analyze osteocyte 3D lacunar distribution and morphology, revealing a role of sp7 in controlling the osteocyte lacunar 3D profile. Our findings suggest potential avenues through which bone quality can be targeted to identify beneficial therapeutics for IVDD.
Highlights
Back pain is a global healthcare concern and economic burden
The nucleus pulposus (NP) is derived from the notochord; it contains chondrocyte-like cells and a gelatinous matrix composed of collagen type 2 and proteoglycans that are vital for the function of the discs and serve as a fluid-filled shock-absorbing cushion
Several studies have highlighted some of the genetics of IVDD7, which include genes involved in bone and cartilage homeostasis[7,8,9]
Summary
Back pain is a global healthcare concern and economic burden It is the leading cause of years lived with disability, with estimates that over 80% of adults will suffer from symptoms at some time in their lives[1]. As the global population ages, a substantial increase in morbidity due to degenerative diseases and back pain is expected;[3] this increase emphasizes the importance of improving our understanding of the causes of IVDD and its relationship with other common degenerative conditions to revise or further develop novel therapeutic strategies. Intervertebral discs (IVDs) connect consecutive vertebral bodies; their main function is mechanical, and they act as shock-absorbing cushions[4]. The NP is derived from the notochord; it contains chondrocyte-like cells and a gelatinous matrix composed of collagen type 2 and proteoglycans that are vital for the function of the discs and serve as a fluid-filled shock-absorbing cushion. While genome-wide association studies (GWAS) have identified an association of a few loci with back pain, IVDD endophenotypes, larger samples, replication, and functional studies are needed to improve reliability and to identify genes associated with IVDD7,8,10,11
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