High levels of periostin correlate with increased fracture rate, diffuse MRI pattern, abnormal bone remodeling and advanced disease stage in patients with newly diagnosed symptomatic multiple myeloma.

E Terpos,M Roussou,E Kastritis,A Papatheodorou,N Kanellias,M Gavriatopoulou,P Kokkoris,T Bagratuni,M A Dimopoulos,C Liakou,D Christoulas,L A Moulopoulos,E Eleutherakis-Papaiakovou,M Migkou,I Panagiotidis

doi:10.1038/bcj.2016.90

Abstract

Periostin is an extracellular matrix protein that is implicated in the biology of normal bone remodeling and in different cancer cell growth and metastasis. However, there is no information on the role of periostin in multiple myeloma (MM). Thus, we evaluated periostin in six myeloma cell lines in vitro; in the bone marrow plasma and serum of 105 newly diagnosed symptomatic MM (NDMM) patients and in the serum of 23 monoclonal gammopathy of undetermined significance (MGUS), 33 smoldering MM (SMM) patients, 30 patients at the plateau phase post-first-line therapy, 30 patients at first relapse and 30 healthy controls. We found high levels of periostin in the supernatants of myeloma cell lines compared with ovarian cancer cell lines that were not influenced by the incubation with the stromal cell line HS5. In NDMM patients the bone marrow plasma periostin was almost fourfold higher compared with the serum levels of periostin and correlated with the presence of fractures and of diffuse magnetic resonance imaging pattern of marrow infiltration. Serum periostin was elevated in NDMM patients compared with healthy controls, MGUS and SMM patients and correlated with advanced disease stage, high lactate dehydrogenase, increased activin-A, increased bone resorption and reduced bone formation. Patients at first relapse had also elevated periostin compared with healthy controls, MGUS and SMM patients, while even patients at the plateau phase had elevated serum periostin compared with healthy controls. These results support an important role of periostin in the biology of myeloma and reveal periostin as a possible target for the development of antimyeloma drugs.

Highlights

Multiple myeloma (MM) is characterized by the presence of osteolytic bone disease
In all these patients periostin was measured in the serum, whereas in 72 newly diagnosed symptomatic MM (NDMM), who gave the respective consent, periostin was measured in their bone marrow plasma
We show for the first time that periostin is elevated in the serum and bone marrow plasma of patients with NDMM and correlates with advanced disease features, such as International Staging System (ISS)-3, diffuse magnetic resonance imaging (MRI) pattern of marrow infiltration and lactate dehydrogenase (LDH) at diagnosis

Summary

Introduction

Multiple myeloma (MM) is characterized by the presence of osteolytic bone disease. Almost 80% of myeloma patients at baseline and up to 90% of patients at some stage of their disease have evidence of bone loss, leading to devastating skeletal complications. Previously known as osteoblast-specific factor, is a disulfide-linked cell adhesion protein that belongs to the fasciclin family and is mainly produced by stromal cells It is a matricellular protein, which is expressed in the periosteum after mechanical stress and is involved in bone formation and normal bone remodeling process.[2,3] The exact role of periostin on bone remodeling is not totally clear to date, it is known that osteoclasts express periostin during in vitro differentiation, whereas the expression of periostin peaks in the early phases of osteoblast differentiation and decreases later at the start of mineralization.[4] Novel data suggest that periostin serves both as a structural molecule of the bone matrix and a signaling molecule through integrin receptors and Wnt-β-catenin pathway, whereby it stimulates osteoblast functions and bone formation.[5] The significance of periostin on bone biology becomes evident by its influence on bone loss in several bone disorders. Recent clinical evidence suggests that periostin stimulates metastatic growth by promoting cancer cell survival, invasion and angiogenesis in several cancers.[10,11,12] Especially, bone metastases from breast cancer induce overexpression of periostin by surrounding stromal cells and serum levels of periostin are elevated in such patients.[13]

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