Calcif Tissue Int (1992) 50:293-294

Calcified Tissue International ~c31992 Springer-Verlag New York Inc.

Letter to the Editor

Etiology of Paget's Disease of Bone: A New Perspective We have read with interest Kahn's [I] editorial about the viral etiology of Paget's disease of bone recently published in Calcified Tissue International. The author gave arguments supporting the concept that osteoblasts rather than osteoclasts were targeted by the putative virus involved in Paget's disease of bone, i.e., the paramyxovirus [t]. We think that this elegant concept agrees with recent advances in the biology of Paget's disease of bone. The purpose of our comment is not to compile the arguments supporting the concept of a viral etiology of Paget's disease of bone [reviewed in 2, 3] but to reconcile the new data on the biology of Paget's disease of bone with the viral etiology of this disease and the osteoblastic target of the putative virus. Recently, Ruther et aL [4] have shown that deregulated c-fos expression interferes with normal bone development in transgenic mice. Actually, bone remodeling abnormalities observed in these transgenic mice are macroscopically and microscopically identical to those observed in patients with a Paget's disease of bone [4]. Furthermore, these mice develop osteosarcomas [5], a major complication of the human Paget's disease of bone, in agreement with the induction of osteosarcoma by the viral oncogene v-fos [6-8]. Thus, an interesting hypothesis is that human Paget's disease of bone could be due to an activation of the c-fos protooncogene in bone cells, perhaps by insertion of a virus such as a paramyxovirus in human osteoblasts. More recently, G. D. Roodman and his colleagues have shown that abnormal virus-infected osteoclasts could be generated in vitro from the bone marrow of patients with Paget's disease of bone [9] and that interleukin-6 (IL-6) was an autocrine/paracrine factor for these osteodasts [I0]. IL-6 is a pleiotropic cytokine with many critical effects in vitro and in vivo [11]. Several points related to IL-6 biology are highly relevant to the etiology of Paget's disease of bone. First, IL-6 is produced in large amounts by osteobtasts, it stimulates bone resorption, and is perhaps a critical cytokine involved in bone remodeling, in vitro and in vivo [12-15]. Second, the production of IL-6 can be induced in fibroblasts and macrophages by viruses, including retroviruses such as paramyxovirus and the human immunodeficiency virus [16, 17]. Thus, it is highly likely that infection of osteoblasts by the putative virus (i.e., the paramyxovirus) involved in Paget's disease of bone could trigger IL-6 production in these cells and could be responsible for a locally IL-6-induced abnormal bone remodeling. Furthermore, it is possible that osteoclasts might also be infected by virus and thus be induced to produce IL-6 also. Under these conditions, IL-6 might be seen as an autocrine/paraerine factor for pagetic osteoclasts [10]. How then to reconcile IL-6 and the observations on the protooncogene c-fos? Walther et al. [19] and Ray et al. [20] have recently demonstrated that there is a 70% nucleotide sequence identity across a 50-nucteotide long stretch of the c-fos enhancer (i.e., the serum responsive enhancer element in the human c-fos gene) and the 5'-

flanking and promoter regions of the human IL-6 gene. As suggested by the same authors, the possibility, therefore, exists that the signals that turn on the IL-6 gene automatically also turn on the c-fos gene transcription through a similar DNA regulatory element. This might occur in human osteobtasts infected with paramyxovirus. Furthermore, the fos-protein does not bind to DNA directly but requires the formation of a complex with another nuclear protein p39, which is the product of the c-jun proto-oncogene [21]. It is of interest to note that IL-6, through the activation of the synthesis of several glycoproteins (i.e., gp 80, gp 130, gp 160), is able to activate the c-jun B gene [I1], a member of the c-jun family [22]. This means that the formation of an active complex c-fos protein + c-jun protein could be obtained through IL-6 activation in osteoblasts. In conclusion, the primary viral infection of human osteoblasts could lead to activation of the IL-6 and c-fos genes, the synthesis of IL-6 and oncogenic proteins, and to a localized abnormal bone remodeling i.e., Paget's disease of bone. Rtgis Bataille Bernard Klein INSERM U291, Immunopathology 34100 Montpellier c6dex, France

References 1. Kahn AJ (1990) The viral etiology of Paget's disease of bone: a new perspective. Calcif Tissue Int 47:127-129 2. Singer FR, Mills BG (1983) Evidence for a viral etiology of Paget's disease of bone. Clin Orthop Rel Res 178:245-251 3. Basle MF, Rebel A, Fournier JG, Russell WC, Matkani K (1987) On the trail of paramyxoviruses in Paget's disease of bone. Clin Orthop Ret Res 217:9-15 4. Ruther U, Garber C, Komitowski D, MOiler R, Wagner EF (t987) Deregulated c-fos expression interferes with normal bone development in transgenic mice. Nature 325:412-,416 5. Grigoradis AE, Wang ZO, Mohle-Steinlein U, Scheltander K~ Wagner EF (I990) Effect of c-fos on bone and cartilage differentiation in transgenic and chimaeric mice. J Bone Miner Res 5 (suppl 2):545 6. Finkel MP, Biskis BO, Tinkins PB (1966) Virus induction of osteosarcomas in mice. Science 151:698-701 7. Huvos AG, Butler A, Bretsky SS (1983) Osteogenic sarcoma associated with Paget's disease of bone. A clinicopathologic study o1"65 patients. Cancer 52:1489--1495 8, Mills BG, Holst PA, Stabile EK, Adams JS, Rude RK, Fernie BF, Singer FR (1985) A viral antigen-bearing cell derived from culture of Paget's bone cells. Bone 6:257-268 9. Fransto A, Mills B, Singer F, Roodman GD (1990) Multinucleated cells formed in long-term marrow cultures from Paget's patients express viral antigens. J Bone Miner Res 5 (suppt 2):791 10. Roodman GD, Kurihara N, Osaki Y, Singer FS (1990) IL-6 is an

Letter to the Editor


11. 12.


14. 15.


autocrine/paracrine factor for pagetic osteoclasts. J Bone Miner Res 5 (suppl 2):793 Hirano T, Akira S, Taga T, Kishimoto T (1990) Biological and clinical aspects of interleukin-6. Immunol Tod 11:443--449 Bowen M, Littlewood AJ, Chapman K, A1-Humidan KA, Hughes DE, Ralston S, Aarden L, Russell RGG (1989) Interleukin-6 production by bone is stimulated by osteotropic agents but does not alter osteoblast activity or bone resorption. J Bone Miner Res 4 (suppl 1):887 Kurihara N, Bertolini D, Soda T, Akiyama Y, Roodman GD (1990) 1L-6 stimulates osteoclast-like multinucteated cell formation in long-term human marrow cultures by inducing IL-1 release. J Immunot 144:4226.-4230 Ischimi Y, Miyaura C, Jin CH (1990). IL-6 is produced by osteoblasts and induces bone resorption. J Immunol 145:32973303 Black KS, Mundy GR, Garrett IR (1990) Intefleukin-6 causes hypercalcemia in vivo and enhances the bone-resorbing potency of interleukin- 1 and tumor necrosis factor by two orders of magnitude in vitro. J Bone Miner Res 5 (suppl 2):787 Seghal PB, Helfgott DC, Santhanam U, Tatter SB, Clarick RH, Ghrayeb J, May LT (1988) Regulation of the acute phase and immune responses in viral diseases. Enhanced expression of the


18. 19.


21. 22.

t32-interferon/hepatocyte stimulating factor/interleukin-6 gene in virus-infected human fibroblasts. J Exp Med 167:1951-1956 Ray A, Tatter SB, May LT, Seghal PB (1988) Activation of the human "f32-interferon/hepatocyte stimulating factor/ interleukin-6 promoter by cytokines, viruses and second messengers. Proc Natl Acad Sci (USA) 85:6701-6705 Birx DL, Redfield RR, Tencer K, Fowler A, Burke DS, Tosato G (1990) Induction of interleukin-6 during human immunodeficiency virus infection. Blood 76:2303-2310 Watther Z, May LT, Sehgal PB (1988) Transcriptional regulation of interferon-132/B celt differentiation factor BSF-2/ hepatocyte-stimulating factor gene in human fibroblasts by other cytokines. J Immunol 140:974-977 Ray A, Sassone-Corsi P, Sehgal PB (1989). A multiple cytokine and second messenger-responsive element in the enhancer of the human interleukin-6 gene: similarities with c-fos gene regulation. Mol Cell Biol 9:5537-5547 Rauscher FJ~ Cohen DR, Curran T, Bos TJ, Vogt PK, Bohmann D, Tjian R, Franza R (1988) Fos-associated protein p39 is the product of the jun proto-oncogene. Science 240:1010-1016 Nakabeppu Y, Ryder K, Nathans D (1988) DNA binding activities of three murine jun proteins: stimulation by Fos. Cell 55:907-915

Etiology of Paget's disease of bone: a new perspective.

Calcif Tissue Int (1992) 50:293-294 Calcified Tissue International ~c31992 Springer-Verlag New York Inc. Letter to the Editor Etiology of Paget's D...
256KB Sizes 0 Downloads 0 Views