Osteoblastogenesis and tumor growth in myeloma

Abstract

Myeloma is associated with suppression of osteoblastogenesis, consequentially resulting in increased osteoclast activity and induction of typical osteolytic bone disease. The molecular mechanisms by which myeloma cells suppress osteoblastogenesis and the consequences of increased osteoblast activity on myeloma cell growth have been partially delineated only recently. Reduced osteoblastogenesis is a consequence of abnormal properties and impaired osteogenic potential of osteoprogenitor cells from myeloma patients and is also the result of production of multiple osteoblastogenesis inhibitors by myeloma cells and by microenvironmental cells within the myelomatous bone. Nevertheless, novel osteoblast-activating agents (e.g. proteasome inhibitor bortezomib) are capable of inducing bone formation in myeloma animal models and clinically. These agents induce increased osteoblast activity, often coupled with a concomitant reduction in osteoclastogenesis, that is strongly associated with reduced myeloma tumor burden. In vitro, osteoblasts, in contrast to osteoclasts, attenuate the growth of myeloma cells from a large subset of patients; potential molecular mechanisms are discussed. These studies suggest that myeloma cells suppress osteoblastogenesis to their advantage and that increased osteoblast activity is a promising approach to treat myeloma bone disease and simultaneously control myeloma development and progression.

Keywords:

• Myeloma
• bone formation
• osteoblasts
• proteoglycans
• bortezomib
• Wnt

Acknowledgments

This work was supported by grants from the National Cancer Institute (CA-093897) (S. Y.) and from the Multiple Myeloma Research Foundation (Senior and Translational Research Award) (S. Y.). The author would like to recognize the efforts of the members of Dr. Yaccoby's laboratory: Xin Li, Angela Pennisi, Wen Ling, Sharmin Khan, Jianmei Chen, Yuping Yang. The author thanks the faculty, staff, and patients of the Myeloma Institute for Research and Therapy for their support, as well as the Office of Grants and Scientific Publications at the University of Arkansas for Medical Sciences for editorial assistance during the preparation of this manuscript.