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Report on the First International Workshop on the CCN Family of Genes J Clin Pathol: Mol Pathol 2001;54:105–107 105 Report on the first international workshop on the CCN family of genes Mol Path: first published as 10.1136/mp.54.2.105 on 1 April 2001. Downloaded from The first international workshop on the CCN family of ingrowth into the growth plate, it probably plays an impor- genes brought together 75 participants coming from tant role in many aspects of bone growth and repair. essentially all laboratories working in this expanding field. Expression of ctgf in newt limb regeneration with or The meeting was a great success, with exceptionally good without denervation was described in a poster presented by quality scientific exchange, and many fruitful personal Moussad et al. Early ctgf expression was detected in diVer- contacts being made. ent cell types. A role for CTGF was proposed in morpho- As can be seen in this meeting summary, major progress genesis (digit indentation of stump) and hypertrophy of has been made in the fields of development and pathobiol- cartilage. Increased ctgf expression after denervation ogy. New aspects concerning the structural basis for some resulted in muscle atrophy. In this system, CTGF was functions of the CCN proteins and their conservation shown to play a role in the inflammatory response, emerged and most certainly constitute exciting avenues for extracellular matrix remodelling, cell proliferation, endo- future research in the CCN field. chondral ossification, and morphogenetic cell death. CTGF-L/rCOP-1/WISP-2 also appears to be implicated Role of the CCN proteins in developmental in osteoblast and chondrocyte function because it is found processes Several reports have confirmed the importance of CCN in high amounts in osteoblasts and stimulates adhesion and proteins in the chondrogenesis and ossification processes. mineralisation of osteoblasts and proteoglycan synthesis in Early studies by L Lau and collaborators had established chondrocytes (presented by S Kumar). that CYR61 was involved in chondrogenesis. The results NOV also appears to be involved in chondrocyte that were presented at this meeting indicated that cyr61 is function and diVerentiation because it is found in the expressed in trophoblasts and spongioblasts and estab- growth plate as well as in endochondromas, where expres- lished a role for CYR61 in the formation of the chorion and sion was generally higher in low rather than high grade its vascularisation, as shown by the eVects of the lesions. In chondrocyte organ cultures, nov expression was recombinant CYR61 protein on cell proliferation, migra- stimulated by parathyroid hormone related protein tion, and attraction of endothelial cells (as shown in in vitro (PTHrP), a regulator of growth plate chondroctye cultures or grafts). Cyr61 knockout of mice resulted in diVerentiation (presented by B Alman). In addition, nov is embryonic lethality as a result of vascular defects in both expressed during the first trimester in the developing embryonic and extraembryonic tissues. musculoskeletal system including the spinal cord, skeletal A major role for CYR61 appears to be in bone signalling. and smooth muscle, and chondrocytes (presented by P It is produced by mesenchymal cells and osteoclasts from Schofield). fracture callus, in matured growth plate chondrocytes, in At early stages of development in the chick embryo, the http://mp.bmj.com/ proliferating osteoblast cell lines, and in primary cultures. expression of nov was detected in dorsal and periventricu- Moreover, expression of cyr61 is stimulated in osteoblasts lar aspects of the neural tube, from 2 days onwards by vitamin D3 and growth factors, all of which are impor- (presented by K Katsube). With this exception, nov tant in bone metabolism (presented by N Scuhtze). expression was restricted to mesodermally derived struc- Results presented by M Takigawa established that tures (predominant in somites and myotomes in areas from connective tissue growth factor (CTGF; highly expressed which the hypaxial musculature originates). NOV was also in chondrocytes, and designated Hcs28 by the authors) is found in the notochord, in the apical ridges of limb buds, on September 27, 2021 by guest. Protected copyright. involved in skeletogenesis not only during prenatal and in the posterior part of branchial arches, particularly in development but also under traumatic conditions and in the second arch. Cos7 cells expressing nov and grafted into bone fracture repair. The eVects of recombinant CTGF the flank of the embryo induced a supernumerary limb and corresponding antibodies on proliferation and diVer- bud-like structure. In ovo electroporation experiments entiation of chondrocytes (proteoglycans and collagen showed that nov is regulated by Wnt1 (reminiscent of synthesis), osteoblasts (mineralisation), and endothelial WISP genes being targets of Wnt regulation). This cells (proliferation, migration, and angiogenesis) were supports an involvement of NOV in ectomesenchymal assessed using in vitro cultures. A paracrine eVect of interactions with a possible dorsalising eVect. CTGF on three cell lines indicated involvement in As in the chick, the expression of nov is essentially endochondral ossification. The role of CTGF in fracture repair suggests future clinical applications. detected in musculoconnective tissues in the lateral part of In a similar manner to CYR61, CTGF also figures dermomyotomes in early mouse embryos and later on in prominently in vascularisation (endothelial cells and myo- the hypaxial muscles, ocular muscles, and blood vessel cardium) and cartilage development (presented by K walls (presented by E Andermacher). The pax3 and nov Lyons). CTGF is strongly expressed in skeletal growth expression patterns suggested that PAX3 and NOV are plates, in particular, in the context of chondrocyte functionally connected in hypaxial myogenesis. Overex- hypertrophy, a necessary maturation step for endochondral pression of nov in embryonic stem (ES) cells in vitro ossification. Overexpression of ctgf after transfection inter- stimulates cell proliferation and survival and early fered with the proliferation of stromal cells in the bone myogenesis, but blocks terminal muscular diVerentiation marrow, articular chondrogenesis, and cartilage hypertro- and the formation of myotubes. Similarly, chimaeric mouse phy, depending on the degree of expression and in associ- fetuses, obtained from the fusion of normal and nov+ ES ation with transforming growth factor â (TGF-â). Further cells, presented with severe malformation in the craniobra- confirmation was obtained from ctgf knockout studies in chial and limb muscles. The systems involved in the nega- mice, where lack of CTGF led to skeletal defects aVecting tive regulation of nov at late stages of myogenesis that allow ribs, sternum, cervical vertebrae, and craniofacial ele- the terminal diVerentiation of muscle are currently being ments. Because CTGF might also induce vascular studied. www.molpath.com 106 Editorial The eVects of NOV on in vitro muscle diVerentiation function during pathological conditions such as inflamma- were exemplified by the capacity of full length mouse NOV tion, wound healing, and atherosclerosis. protein to induce a block of diVerentiation of 10T1/2 The expression of the WISP genes had been reported to Mol Path: first published as 10.1136/mp.54.2.105 on 1 April 2001. Downloaded from fibroblasts, as opposed to truncated NOV, which induced be regulated by Wnt. In addition to nov being another tar- complete diVerentiation (poster presented by D Tahri). get of Wnt regulation (see above), a novel gene, wise, bear- DiVerential expression of NOV was also observed in satel- ing a weak homology to the CCN family members may lite stem cells undergoing muscle diVerentiation, and in play a role in the Wnt signalling pathway because muscle regeneration (poster presented by Cherel et al). immunoprecipitation studies suggest it binds to the Wnt A striking example for the conservation of CCN protein receptor Frizzled (presented by N Itasaki ). W Kutz exam- functions throughout species was provided by studies per- ined the expression pattern of WISP-3 in eukaryotic cells. formed with Xenopus laevis (presented by B Latinkic). Previous work has shown that loss of function mutations in Cloning and sequencing of cyr61 in this species had WISP-3 are found in patients with the heritable skeletal revealed a high phylogenetic conservation of this gene. In disorder progressive pseudorheumatoid dysplasia, impli- situ hybridisation allowed the detection of maternal cyr61 cating a role for WISP-3 in skeletal growth and homeosta- RNAs up to the cleavage stage and embryonic ones from sis. the neurulation stage, essentially in the dorsal aspect of the A large number of reports now indicate that ctgf expres- embryo in mesodermal structures first (somites, noto- sion is regulated by TGF-â in many instances. However, an chord, branchial arch mesenchyme). Later on (from the tail increasing body of evidence suggests that this relation is not bud stage) the expression was also detected in ectodermal obligatory. A TGF-â response element that is distinct from tissues (otic vesicles and neural tube) and finally in the the previously identified TGF-â response element was dis- heart of the tadpole. A miss-expression of the cyr61 gene cussed. A Leask showed that the induction of CTGF by (complete or partial) induced by injections in the ventral TGF-â is repressed by tumour necrosis factor á (TNF-á) regions of the embryo caused several malformations, through a nuclear factor êB (NFêB) dependent
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