Canonical Wnt signaling and caveolae play a role in intervertebral disc degeneration; the continuing saga of the mysterious notochordal cell

Over the past few decades small animal models mainly involving rodents and rabbits have been developed whereby needle puncture, stab incision or enzymatic approaches have been validated to create the degenerative disc. Although important, these models continue to be plagued by biological attributes that limit applicability to the human condition. However, the fascinating story of two naturally occurring subspecies of canine, the non-chondrodystrophic and chondrodystrophic canine, provides us with an animal model that differentially is protected from the development of degenerative disc disease. Here, Smolders and colleagues provide the first steps to understanding some of the secrets held by man's best friend.

obvious supportive function, the IVD is an isolated, hypoxic, ischemic and immune privileged tissue compart ment that poses unique challenges with respect to regenerative strategies [3]. Th e cells within the NP have evolved to tolerate the otherwise 'hostile' environment of low oxygen levels and tenuous nutrient and gas diff usion properties that are in turn mediated by the endplates through delicate homeostatic regulatory mechanisms [3,4]. However, with respect to intrinsic cellular mechanisms concerning degenerative disc disease (DDD) progres sion, there is still much to be learned.
With respect to understanding salient diff erential mecha nisms concerning DDD, nature has provided an interesting anomaly whereby two naturally occurring canine subspecies are diff erentially protected from degenerative change; the NCD and CD canine [5,6]. Th ese two canine sub-species are defi ned to a large degree by their diff erential susceptibility to DDD with the NCD canine NP protected from developing DDD and retaining large populations of notochordal cells (NCs) within their NP throughout life [6,7]. Th e CD canine on the other hand develops DDD early in life in a similar fashion to that of humans and is largely NC-defi cient [5,6]. A number of studies have examined NC interaction with NP cells and have determined that NCs confer a benefi cial role upon the maintenance of the healthy IVD NP [7][8][9][10].
Amongst a number of important unanswered questions are the mechanisms whereby NCs persist in the NPs of NCD dogs and disappear in CD animals. Smolders and colleagues report that when NC populations decline during early DDD there are changes in a number of signaling pathways specifi cally including down-regu lation of both canonical Wnt signaling and caveolin-1 expression. Th ese changes in cellular signaling pathways suggest that the Wnt/β-catenin signaling cascade may be pivotal for the preservation of the NC-rich NP phenotype and perhaps also maintenance of the healthy NP phenotype. Gene expression of the important marker of

Abstract
Over the past few decades small animal models mainly involving rodents and rabbits have been developed whereby needle puncture, stab incision or enzymatic approaches have been validated to create the degenerative disc. Although important, these models continue to be plagued by biological attributes that limit applicability to the human condition. However, the fascinating story of two naturally occurring subspecies of canine, the non-chondrodystrophic and chondrodystrophic canine, provides us with an animal model that diff erentially is protected from the development of degenerative disc disease. Here, Smolders and colleagues provide the fi rst steps to understanding some of the secrets held by man's best friend.
Wnt signaling (axin2) was reported to be reduced in canine discs displaying predominantly chondrocyte-likecell (CLC) groups compared to the NC-rich and mixed groups (50:50 NCs:CLCs) in both NCD and CD dogs. However, when comparing the two sub-species irrespective of their histopathological classifi cations, the CD dog NPs demonstrate signifi cantly higher levels of axin2 gene expression than NCD dogs. Th ese diff erences suggest that important changes in Wnt/β-catenin signaling occur with the alteration of the NP from the NC-rich to the more 'chondrifi ed' CLC disc that is more typical of the degenerative phenotype. Th e important and unanswered questions with respect to NC preservation are how these processes work and why is there an alteration in the important Wnt/β-catenin signaling pathway? β-Catenin signaling mediates in part cadherin-related cytoskeletal organization and cell adhesion. Th e report by Smolders and colleagues suggests that increased Wnt/ β-catenin signaling is associated with the NP of dogs that suff er premature DDD and that the preservation of NCs seems to be integral (in an as of yet unclear fashion) to what may be homeostatic regulatory Wnt/β-catenin signal ing. Down-regulation of caveolin-1 gene and protein expression was observed to accompany the loss of NCs, which in turn is associated with 'chondrifi cation' of the disc and the development of a degenerative phenotype. However, in addition to various aspects of tissue maintenance the Wnt/β-catenin signaling networks are also signifi cantly involved with the proliferation and diff erentiation of stem cells. Given that both of these subspecies of dog contain NP progenitor/stem cells and NP cells but varying populations of NCs, it leads one to wonder what impact the Wnt/β-catenin signaling as detailed by Smolders and colleagues may have amongst this diverse cellular population and what are the implications in terms of susceptibility to DDD? Understanding the respective signaling (Wnt/β-catenin?) pathways will be a daunting task but such knowledge might provide vital information concerning the propensity of the NP to suff er DDD.
Th e manuscript by Smolders and colleagues suggests that the maintenance of the NC-rich/non-degenerative NP phenotype may require appropriate homeostatic regu lation involving caveolae, caveolin-1 and Wnt/βcatenin signaling pathways. In their paper these authors indicated that the NP of wild-type mice was rich in viable NCs, whereas the NP of caveolin-1 knockout mice contained chondroid-like matrix with mainly apoptotic, small, rounded cells. Taken together this leads one to ponder if part of the secret to avoiding DDD may lie within restoration of the homeostatic communication/ regulation between the unique cells within the IVD NP, or is DDD susceptibility a function of the peculiarities of the canine sub-species and simply a genetic anomaly [11]? It is tantalizing to consider that the human condition may actually resemble that of man's best friend-who may yet have important lessons to teach us.