ARTHRITIS & RHEUMATISM Vol. 65, No. 10, October 2013, pp 2634–2644 DOI 10.1002/art.38075 © 2013, American College of Rheumatology Impaired Intervertebral Disc Development and Premature Disc Degeneration in Mice With Notochord-Specific Deletion of CCN2 Jake Bedore, Wei Sha, Matthew R. McCann, Shangxi Liu, Andrew Leask, and Cheryle A. Se ´guin Objective. Currently, our ability to treat inter- vertebral disc (IVD) degeneration is hampered by an incomplete understanding of disc development and aging. The specific function of matricellular proteins, including CCN2, during these processes remains an enigma. The aim of this study was to determine the tissue-specific localization of CCN proteins and to char- acterize their role in IVD tissues during embryonic development and age-related degeneration by using a mouse model of notochord-specific CCN2 deletion. Methods. Expression of CCN proteins was as- sessed in IVD tissues from wild-type mice beginning on embryonic day 15.5 to 17 months of age. Given the enrichment of CCN2 in notochord-derived tissues, we generated notochord-specific CCN2–null mice to assess the impact on the IVD structure and extracellular matrix composition. Using a combination of histologic evaluation and magnetic resonance imaging (MRI), IVD health was assessed. Results. Loss of the CCN2 gene in notochord- derived cells disrupted the formation of IVDs in embry- onic and newborn mice, resulting in decreased levels of aggrecan and type II collagen and concomitantly in- creased levels of type I collagen within the nucleus pulposus. CCN2-knockout mice also had altered expres- sion of CCN1 (Cyr61) and CCN3 (Nov). Mirroring its role during early development, notochord-specific CCN2 deletion accelerated age-associated degeneration of IVDs. Conclusion. Using a notochord-specific gene tar- geting strategy, this study demonstrates that CCN2 expression by nucleus pulposus cells is essential to the regulation of IVD development and age-associated tis- sue maintenance. The ability of CCN2 to regulate the composition of the intervertebral disc suggests that it may represent an intriguing clinical target for the treatment of disc degeneration. Globally, the prevalence of low back pain is increasing at an alarming rate, with the most recent systematic review reporting a lifetime prevalence of 39%, which is predicted to increase substantially over the coming decades as the population ages (1). Inter- vertebral disc (IVD) degeneration, an underlying cause of low back pain, begins with changes in the cellular microenvironment that are initiated long before the appearance of associated symptoms, such as decreased mobility and acute or chronic pain (2). The lack of effective treatment for this widespread clinical problem is related to our limited understanding of the mecha- nisms that regulate the processes of IVD development, maintenance, and degeneration. In particular, there is an incomplete understanding of the relative importance of individual growth factors, secreted molecules, and matrix components that constitute the unique micro- environment of the IVD. Supported by the Canadian Institutes of Health Research (CIHR) (grants MOP-77603 to Dr. Leask and MOP-115718 to Dr. Se ´guin). Mr. Bedore and Mr. McCann’s work was supported by the CIHR Joint Motion Program/Training Program in Musculoskeletal Health Research and Leadership. Dr. Sha is recipient of a Postdoc- toral Fellowship from the Canadian Scleroderma Research Group. Mr. McCann is also recipient of a CIHR Doctoral Research award. Dr. Se ´guin is recipient of a Scholar award from The Arthritis Society/ Canadian Arthritis Network. Jake Bedore, HBSc, Wei Sha, PhD (current address: Chao- yang Hospital, Chaoyang, Beijing, China), Matthew R. McCann, BSc, Shangxi Liu, PhD, Andrew Leask, PhD, Cheryle A. Se ´guin, PhD: Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada. Dr. Leask owns stock or stock options in FibroGen. Address correspondence to Cheryle A. Se ´guin, PhD, Depart- ment of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada. E-mail: cheryle.seguin@schulich.uwo.ca. Submitted for publication November 20, 2012; accepted in revised form June 25, 2013. 2634