Osteoclast-derived activity in the coupling of bone formation to resorption T. John Martin 1 and Natalie A. Sims 2 1 St. Vincent’s Institute of Medical Research, 9 Princes Street, Fitzroy VIC 3065, Australia 2 The University of Melbourne Department of Medicine, St. Vincent’s Hospital, 41 Victoria Parade, Fitzroy VIC 3065, Australia The cells of bone and the immune system communicate by means of soluble and membrane-bound cytokines and growth factors. Through local signalling mechan- isms, cells of the osteoblast lineage control the for- mation and activity of osteoclasts and, therefore, the resorption of bone. Both T and B lymphocytes produce activators and inhibitors of osteoclast formation. A local ‘coupling factor’ linking bone resorption to subsequent formation in the bone multicellular unit (BMU) has long been proposed as the key regulator of the bone remodel- ling process, but never identified. There is evidence in support of the view that the coupling mechanism is dependent on growth factors released from the bone matrix during resorption, or is generated from maturing osteoblasts. We argue that osteoclasts contribute in important ways to the transiently activated osteoclast, and stimulate osteoblast lineage cells to begin replacing the resorbed bone in each BMU. Bone remodelling The remodelling of bone consists of a strict coupling of bone resorption and formation that continues throughout life and is necessary not only for skeletal growth but also to maintain normal bone structure [1–5]. The process begins with the resorption of a volume of bone by osteoclasts followed by new bone formation by osteoblasts, with a positive balance during growth and a negative balance with ageing. This process takes place in ‘bone multicellular units’ (BMUs) asynchronously throughout the skeleton. If the volume of bone resorbed exceeds the volume formed, bone loss results, producing bone fragility and leading to osteoporotic fractures. Circulating hormones, such as parathyroid hormone (PTH) and gonadal steroids, exert controlling influences on bone remodelling, but crucial regulation is provided by many cytokines and growth factors that are the products of bone cells and the immune system. Much has been learned during the past five years of the cellular and molecular mechanisms by which osteoclast precursors are recruited and induced to differentiate into active mature osteoclasts. We will focus upon the reverse pathway in bone remodelling, through which osteoblasts are instructed to replace the bone that has been resorbed. Based on evidence from human and mouse genetics, in addition to animal and human pharmacological studies, we propose that activated osteoclasts are the source of the activity that is necessary for control of the bone formation response in remodelling. Intercellular communication in bone: osteoclast formation The importance of local intercellular communication to the regulation of bone-cell function became established after it was proposed that the formation and activity of osteoclasts is controlled by cells of the osteoblast lineage [6]. Osteoclasts, which are the only cells capable of resorb- ing bone, are multinucleated giant cells formed from hematopoietic precursors of the monocyte and macro- phage series. They attach to the bone surface, sealing a resorbing compartment that they acidify by secreting H C ions, facilitating dissolution of the bone mineral and thereby exposing the organic matrix to proteolytic enzymes that degrade it [7]. Osteoclast differentiation is supported by cells relatively early in the osteoblast lineage that express membrane-bound receptor activator of NF-kB ligand (RANKL) and macrophage-colony stimulat- ing factor (M-CSF) (Figure 1) [7]. Proximity between osteoblastic lineage and hemato- poietic cells is required for RANKL and M-CSF to bind to their respective receptors [receptor-activator of NF-kB (RANK) and the M-CSF receptor (c-fms)], which are expressed by monocyte and macrophage lineage cells, thereby stimulating some of these to form osteoclasts. This process is also regulated by a secreted decoy receptor of RANKL, osteoprotegerin (OPG), which functions as a para- crine inhibitor of osteoclast formation [8]. The physiological importance of these recent discoveries has been established by studies in genetically altered mice [9,10]. Finally, T and B cells produce several cytokines that either promote or inhibit osteoclast formation. Some of these function locally during physiological bone remodel- ling, but many contribute to the processes involved in inflammatory bone diseases, such as rheumatoid arthritis and periodontal disease [11]. Despite significant advances in understanding how the osteoblast and immune lineages influence osteoclast Corresponding author: Martin, T.J. ( jmartin@svi.edu.au). Available online 8 January 2005 Opinion TRENDS in Molecular Medicine Vol.11 No.2 February 2005 www.sciencedirect.com 1471-4914/$ - see front matter Crown Copyright Q 2004 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2004.12.004