Roles of Wnt signals in bone resorption during physiological and pathological states

REVIEW

Roles of Wnt signals in bone resorption during physiological and pathological states

Kazuhiro Maeda &Naoyuki Takahashi &Yasuhiro Kobayashi

Received:23June 2012/Revised:28September 2012/Accepted:17October 2012/Published online:31October 2012#Springer-Verlag Berlin Heidelberg 2012

Abstract Osteoclasts,multinucleated giant cells,are re-sponsible for bone resorption in physiological and patho-logical conditions such as osteoporosis and rheumatoid arthritis.Osteoclasts develop from the monocyte/macro-phage lineage under the strict control of bone-forming osteoblasts.Osteoblast-lineage cells express two cytokines essential for osteoclast differentiation,colony-stimulating factor-1,and receptor activator of nuclear factor κB ligand (RANKL)and also express osteoprotegerin,a soluble decoy receptor for RANKL.The signaling molecule Wnt has been shown to be important for the differentiation of osteoblasts through β-catenin-dependent canonical and β-catenin-independent noncanonical pathways.Recent studies have established that Wnt-mediated signals are also crucial for bone resorption in both physiological and pathological con-ditions.In this review,we introduce recent advances in roles of Wnt signaling in bone formation and bone resorption.Keywords Osteoclast .Osteoblast .Wnt5a .Ror2.Bone resorption .Rheumatoid arthritis

Introduction

Bone is continuously destroyed and reformed in vertebrates to maintain bone volume and calcium homeostasis [1].

Osteoblasts and osteoclasts are specialized cells responsible for bone formation and bone resorption,respectively.Osteo-clasts develop from monocyte/macrophage lineage precur-sors under the strict regulation of osteoblasts,osteocytes (referred to as “osteoblast-lineage cells ”in this review),and bone marrow stromal cells [2–5].

Osteoblast-lineage cells express two cytokines essential for osteoclast differentiation,colony-stimulating factor-1(CSF-1),and receptor activator of nuclear factor κB ligand (RANKL)[6,7](Fig.1).Osteoblasts constitutively express CSF-1,whereas RANKL is inducibly expressed in osteoblasts in response to bone resorption-stimulating factors such as 1α,25dihydroxyvitamin D 3(1,25D 3),parathyroid hormone,and in-terleukin (IL)-11[8].Osteoclast precursors express CSF-1receptor (CSF-1r)and RANK (RANKL receptor),and differ-entiate into osteoclasts in the presence of CSF-1and RANKL.Osteoblasts also produce osteoprotegerin (Opg),a soluble decoy receptor for RANKL [9].Opg inhibits osteoclastogene-sis by blocking the RANKL –RANK interaction.Both RANKL -[10]and RANK -deficient mice [11]develop severe osteopetrosis with no osteoclasts in bone.In contrast,Opg -deficient mice exhibit severe trabecular and cortical bone porosity with enhanced osteoclastic bone resorption [12,13].Several studies in the past few years have identified additional mechanisms whereby osteoblast-lineage cells and osteoclastic cells interact with one another to positively and negatively regulate their differentiation and functions.Ephrin B2,a ligand expressed by osteoclasts and osteoclast precursors,and its receptor Eph 4on osteoblast-lineage cells inhibit osteoclastogenesis through ephrine B2due to sup-pression of c-Fos expression [14].Recently,osteoblast-derived Semaphorin 3A (Sema3A),known as an axon guid-ance molecule,was identified as an inhibitor of osteoclasto-genesis and also as a stimulator of osteoblastogenesis [15].Sema3A binds a receptor complex consisting of neuropilin 1(Npr1)and Plexin-A in osteoclast precursors and prevents

K.Maeda :N.Takahashi :Y .Kobayashi (*)

Institute for Oral Science,Matsumoto Dental University,1780Gobara,Hiro-oka,

Shiojiri,Nagano 399-0781,Japan e-mail:ykoba@po.mdu.ac.jp

K.Maeda

Department of Orthopedic Surgery,

The Jikei University School of Medicine,3-25-8Nishi-Shinbashi,Minato-ku,Tokyo 105-8461,Japan

J Mol Med (2013)91:15–23DOI 10.1007/s00109-012-0974-0