Myelofibrosis with myeloid metaplasia (MMM) is a clonal stem cell disease that is associated with distinct bone marrow histologic changes that include myelofibrosis, osteosclerosis, and angiogenesis. Chagraoui and colleagues have recently demonstrated, using a combination of blood cell transplantation and gene knockout experiments, the essential role of blood cell–derived transforming growth factor beta 1 (TGF-β1) in the development of myelofibrosis in thrombopoietin (TPO)–induced MMM-like disease in mice (Blood. 2002;100:3495-3503). In the current issue (page 2973), the same group of investigators, using a similar experimental design, address the mechanism of osteosclerosis in the aforementioned animal model of MMM. The protein of focus this time was osteoprotegerin (OPG), a known inhibitor of bone resorption.
Osteoclast differentiation and activation is facilitated by the receptor-ligand interaction between RANK (receptor activator of NF-κB) and RANK ligand (RANKL). OPG, secreted by bone marrow stromal cells and osteoblasts, is a decoy receptor of RANKL and thus interferes with RANK-RANKL binding with the net result of impaired bone resorption. The study mice in the current report included both wild-type and mutant (OPG−/−/OPG−/−) recipient-donor pairs in different combinations. The results suggest that the presence of an intact OPG gene in bone marrow stroma, but not in blood cells, was imperative for the development of TPO-induced osteosclerosis in mice. Additional experiments suggested that stromal OPG up-regulation may not be mediated by TGF-β1.
The current study is one of a series of elegant experiments by the above mentioned group from France concerning the pathogenesis of MMM. The aforementioned set of findings are consistent with existing circumstantial evidence that implicates TGF-β1 and related cytokines, derived from clonal megakaryocytes/monocytes, as having either a direct or an indirect (via up-regulation of stromal OPG and possibly other secreted molecules) influence on the bone marrow microenvironment in MMM. The study raises additional questions including the identity and source of the cytokine responsible for stromal OPG up-regulation and other biologic effects of interference with the RANK-RANKL interaction in MMM. Nevertheless, the availability of such information as well as suitable animal models should allow the development of pathogenesis-targeted therapeutic activities including pharmacologic manipulation of the OPG-RANKL-RANK axis.
