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Osteoprotegerin Ann Rheum Dis 2001;60:iii81–iii84 iii81 Ann Rheum Dis: first published as 10.1136/ard.60.90003.iii81 on 1 November 2001. Downloaded from Osteoprotegerin U Feige Osteoclast diVerentiation and activation resistant alkaline phosphatase (TRAP), cathep- DiVerentiation, activation, and survival of sin K, calcitonin, and vitronectin receptors (for osteoclasts are regulated by the balance be- review see Chambers22). A mature osteoclast tween RANKL (RANK ligand) and osteopro- forms a ruZed border, an actin ring, and a tegerin (OPG). OPG is also known as osteo- sealed or clear zone and will form a resorption clast inhibitory factor (OCIT) and is a tumour pit on dentin slices.12 20 23 24 However, there are necrosis factor (TNF) receptor family mem- diVerences between in vitro generated osteo- ber, which is found as a “decoy” receptor only clasts and harvested osteoclasts ex vivo. One because of the lack of a membrane spanning such diVerence is the ability of interleukin 1 domain.12 RANKL is a TNF family member (IL1) to induce an actin ring in in vitro gener- 25 and is also known as osteoprotegerin ligand ated but not in ex vivo osteoclasts. (OPG-L), or osteoclast diVerentiation factor (ODF), or TNF related, activation-induced cytokine (TRANCE).3–5 RANKL exhibits its Osteoclast survival activity on cells through RANK (receptor acti- Survival of mature osteoclasts is dependent on vator of NF-êB), another membrane bound the presence of RANKL,16 though other factors member of the TNF receptor family.6–11 In such as IL1 can promote osteoclast survival, bone marrow, RANKL is produced by osteo- too.25 If osteoclast survival is not suYciently blasts and both osteoblastic and fibroblastic supported osteoclasts will undergo apopto- 17 26 stromal cells. The production of RANKL is sis. In fact, apoptotic osteoclasts in low induced by most (all?) known inducers of bone numbers can be detected after one week in resorption and hypercalcaemia.12–16 Precursor bone marrow cultures driven by M-CSF and 17 cells in bone marrow exposed to M-CSF RANKL. However, if survival factors are (monocyte/macrophage colony stimulating withdrawn, all osteoclasts will undergo apopto- Inflammation Group, sis quickly.17 These eVects can also be demon- Department of factor or CSF-1) and RANKL will diVerentiate 17 26 Pharmacology/Pathology, within one week to mature osteoclasts.3 Both strated in vivo. For example, in mice treated Preclinical with 10 mg/kg OPG intravenously all osteo- M-CSF and RANKL are necessary and suYcient 17 Development, Amgen for this process,17–19 whereas RANKL but not clasts disappear within 48 hours. Interest- Inc, Thousand Oaks, ingly, within 7–10 days osteoclasts return and M-CSF will activate mature osteoclasts to California, USA can be found in normal numbers and typical resorb bone.20 OPG added to such bone U Feige locations in these mice.17 marrow cultures will inhibit the process of Correspondence to: osteoclast generation reversibly.17 18 21 This can Dr U Feige, Mail Stop http://ard.bmj.com/ 15–2-A, One Amgen Center be shown by either removing the OPG after a Drive, Amgen Inc, Thousand few days or by adding more RANKL to the Lessons from transgenic and knockout Oaks, CA 91320–1799, USA cultures, both of which will result in renewed mice [email protected] osteoclast diVerentiation. Mature osteoclasts Osteoclasts and osteoblasts drive bone remod- Accepted 28 June 2001 are characterised by markers such as tartrate elling, a continuous process of osteoclasts resorbing bone and osteoblasts laying down 1,25(OH)2-D3 new bone. Bone resorption is necessary for skeletal growth as well as tooth eruption.27 on September 28, 2021 by guest. Protected copyright. Excess RANKL activity as in OPG−/− mice PTH results in spontaneous fractures and vertebral 28 PTHrp deformities. Studies using knockout and transgenic mice have shown that skeletal growth is normal in OPG knockout mice Osteoclast (which have high net RANKL levels and show PGE2 RANKL differentiation marked osteoporosis)28 29 and OPG transgenic and activation mice (which have low net RANKL levels and show osteopetrosis).130 In contrast, in IL1 RANKL−/− and RANK−/− mice skeletal 931 TNFα growth is impaired. This illustrates that bio- logically there is quite a diVerence between low OPG RANKL levels or no RANKL at all. Without IL11 inhibits RANKL (or RANK) tooth eruption cannot LIF occur (RANKL−/− or RANK−/− mice), whereas with a little RANKL tooth eruption is IL6 normal (OPG transgenic mice). Although cells of the macrophage lineage Oncostatin M also express RANK, it is interesting to note that Figure 1 The balance of RANKL and osteoprotegerin (OPG) controls osteoclast activity. macrophage diVerentiation is normal in OPG Most (all?) known inducers of bone resorption and hypercalcaemia act indirectly through production of RANKL, hence OPG can be used pharmacologically to control osteoclast transgenic and RANKL−/− mice and thus activity independent of the inducing cytokine. seems to be independent of RANKL.131 www.annrheumdis.com iii82 Feige Ann Rheum Dis: first published as 10.1136/ard.60.90003.iii81 on 1 November 2001. Downloaded from http://ard.bmj.com/ on September 28, 2021 by guest. Protected copyright. Figure 2 Administration of recombinant osteoprotegerin (OPG) alleviates bone destruction in arthritis. (A, B, and C) Tibiotarsal (“ankle”) joint of a normal Lewis rat (A) compared with severely inflamed joints of animals with advanced mycobacterial-induced adjuvant arthritis (B, C). Rats given OPG at 4 mg/kg/day subcutaneously for seven days beginning at the onset of clinical arthritis, retained skeletal integrity (C), whereas untreated rats did not (B). The arrowhead denotes the junction of the growth plate with cortical bone; the growth plate is destroyed in untreated arthritic rats (B). (D, E, and F) Bones and cartilage of the proximal intertarsal joint of normal (D) and OPG treated (F) arthritic rats are intact. In contrast, bone is eroded and cartilage matrix is degraded (denoted by pallor) in untreated arthritic rats (E). Asterisks denote inflammation. Stains: haematoxylin and eosin (A-C), toluidine blue (D-F). Photo courtesy of Dr Brad Bolon. Hypercalcaemia histologically17 but which show functional se- RANKL treatment of mice results in induction, quelae, such as hypercalcaemia.312 Known diVerentiation, and activation of osteoclasts inducers of bone resorption and hypercalcae- which can be demonstrated and quantified mia, such as IL1, TNFá, parathyroid hormone www.annrheumdis.com Osteoprotegerin iii83 Ann Rheum Dis: first published as 10.1136/ard.60.90003.iii81 on 1 November 2001. Downloaded from (PTH), PTH related peptide (PTHrp), vitamin allowed for the diVerentiation of osteoclasts 35 39 D3 (1,25(OH)2-D3), etc, have been tested alone only if M-CSF was also present. This eVect and jointly with OPG. In all cases OPG was inhibited by addition of OPG to the bone prevented the induction of hypercalcaemia, marrow cultures. Furthermore, formalin fixed, indicating that all those inducers act indirectly activated T cells could substitute for RANKL, through the induction of RANKL.15 This which indicates that RANKL is active both in conclusion is supported by the fact that injection soluble and in the cell surface bound form. of RANKL, IL1â, TNFá, PTHrp, or Both activated CD4 and CD8 T cells can sup- 40 1,25(OH)2-D3 into RANK−/− mice fails to port osteoclast diVerentiation. As many other induce hypercalcaemia.9 These studies and oth- cytokines (IL1, TNFá, IL6, interferon ã, IL3, ers not reviewed here led to the view, depicted in etc) which induce RANKL in osteoblasts and fig 1, of RANKL as a unique cytokine in osteo- osteoblastic stromal cells are generated in such clast diVerentiation, activation, and survival. T cell cultures, formalin fixed, activated T cells from RANKL−/− mice were added to bone Tumours marrow cells and found not to induce osteo- Many tumour types metastasise into bone. clasts.35 This indicates that it is the surface These eVects can be mediated through PTHrp bound RANKL (and not other factors) on T or IL6, other inducers of bone resorption. Sub- cells which drives osteoclast diVerentiation in jects with a tumour often show hypercalcae- this cell culture system.35 mia. In mouse tumour models, such as the C26 (originally derived from an adenocarcinoma) OPG protects bone in arthritis model, it has been shown that OPG treatment The above findings prompted us to look into T dose dependently prevents tumour-induced cell mediated autoimmune diseases and bone hypercalcaemia.32 Furthermore, OPG can also eVects. Mycobacteria-induced adjuvant arthri- reverse tumour-induced hypercalcaemia in tis in Lewis rats was chosen as a model. Severe these models.32 Interestingly, OPG treatment polyarthritis with extensive joint destruction is can prevent osteolysis and tumour metastasis induced in these rats by an injection of a into bone.33 The data demonstrate that tumour suspension of heat killed mycobacteria in oil at cell derived inducers of bone resorption, such the base of the tail.41 Nine days later clinical as PTHrp, IL6, or TNF , act indirectly á symptoms of disease, paw swelling, and weight through increases in RANKL. loss begin, and disease severity is monitored by their daily measurement. Bone and cartilage Activated T cells produce RANKL destruction in this model is very rapid. By day Other cells besides osteoblasts and osteoblastic 16 significant loss of bone has occurred as stromal cells can also produce RANKL. Inter- shown by erosions and by significant loss of estingly, RANKL is produced
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