ReviewAn overview of the regulation of bone remodelling at the cellular level
Highlights
► Bone remodelling is a complex process involving multiple cell types. ► Cells involved produce various cytokines that have autocrine and paracrine activity. ► Multicellular communication is important for control of bone remodelling. ► Aberrant remodelling results in diseases such as osteoporosis and Paget's disease.
Introduction
Bone is a rigid yet dynamic organ that is characterised as a type of connective tissue. Biochemically, it is defined by a mixture of inorganic elements and an organic matrix. In order to maintain its structural integrity, and to fulfil its role in mineral homeostasis, bone is continuously moulded, shaped and repaired, a process termed remodelling. Bone remodelling is the predominant metabolic process regulating bone structure and function during adult life [1], [2]. Remodelling is a complex, tightly regulated process carried out by two key cell types: osteoclasts and osteoblasts. Osteoclasts are the principal resorptive cell of bone, playing a role in the formation of the skeleton and regulation of bone mass. Osteoblasts are specialised bone forming cells that synthesise bone matrix, regulate mineralisation and finally differentiate into osteocytes or bone lining cells. The cellular coupling between the activities of the osteoclasts and osteoblasts is highly regulated by local and systemic factors to maintain bone homeostasis [3]. An imbalance in the bone remodelling process, favouring either osteoclast or osteoblast activity, leads to a number of clinical disease conditions including osteopenia, osteoporosis and osteopetrosis. The exact mechanisms responsible for aberrant bone remodelling are still largely unclear. Therefore, understanding the cellular and molecular mechanisms involved in bone remodelling may provide important insight(s) for therapeutic development.
Section snippets
The bone remodelling unit
Bone remodelling occurs through the concerted action of a functional cohort of cells termed the basic multicellular unit (BMU). The BMU consists of the osteoclasts resorbing bone, the osteoblasts replacing bone, the osteocytes within the bone matrix, the bone lining cells covering the bone surface and the capillary blood supply (Fig. 1). The remodelling cycle begins with an initiation phase that includes the recruitment of osteoclast precursors, their differentiation into mature osteoclasts as
Osteoclasts
Osteoclasts are multinucleated, giant cells formed by the fusion of mononuclear progenitors of the monocyte/macrophage family in a process termed osteoclastogenesis [2]. Osteoclasts are located on endosteal surfaces within the Haversian system and on the periosteal surface beneath the periosteum. Osteoclasts are usually rare cells in the bone with only two to three per μm3 [7]. Osteoclasts exist in two functional states, the motile and the resorptive phases. During the motile state they migrate
Osteoblasts
Osteoblasts are the only cell type responsible for bone formation. They originate from mesenchymal stem cells that have the potential to differentiate into mature osteoblasts [49], [50]. There are four maturational stages that have been identified in osteoblast differentiation: the preosteoblast, osteoblast, osteocyte and bone-lining cell. Provided the appropriate stimuli are present, the mesenchymal stem cells form preosteoblasts. Histologically these cells resemble osteoblasts and stain
Osteocytes
Osteocytes are terminally differentiated osteoblasts that incorporate into the newly formed bone matrix [82]. These cells are smaller than osteoblasts and have lost many of their cytoplasmic organelles [83]. Osteocytes lie within lacunae in the newly formed bone matrix where they reside for long periods of time but ultimately undergo apoptosis. Osteocytes are spatially isolated from one another; however, they extend long filipodial extensions, which are rich in actin cytoskeleton, connecting
Bone lining cells
A subset of osteoblasts will differentiate into bone lining cells. These cells line the majority of bone surfaces that are not being remodelled. It has been proposed that bone lining cells play a role in bone remodelling by preventing the inappropriate interaction of osteoclast precursors with the bone surface. It is thought that the signals that initiate osteoclast formation may stimulate the bone lining cells to prepare for bone resorption, through the actions of collagenase which digests a
Osteomacs
Osteomacs are resident tissue macrophages present on or near the periosteal and endosteal surfaces. They are located within three cells of a bone surface and are often intercalated or associated with bone lining cells. During bone modelling osteomacs form a canopy-like structure over mature osteoblasts [99], [100]. Osteomacs regulate osteoblast mineralisation as evidenced by in vitro and in vivo studies showing that depletion of osteomac populations results in reduced osteoblast mineralisation
Vascular endothelial cells
A vital, but often overlooked, component of the BMU is the capillary that supplies oxygen and nutrients, and removes calcium and waste products of resorption. Bone is one of the most highly vascularized tissues and angiogenesis plays a pivotal role in bone formation, remodelling and healing [98], [103]. The blood supply to bone is essential for maintenance of bone mineral density and bone structure. Pathological situations resulting in loss of the bone blood supply lead to bone death, such as
Lymphocytes — T cells and B cells
The relationship between the immune and skeletal systems has been studied since the early 1970s and as such the term osteoimmunology was created to describe the overlap between these fields (for a detailed review on osteoimmunology see [121]). Given that immune cells and haematopoietic cells originate in the bone marrow it is not surprising that there is cross-talk between the two systems. A number of factors secreted by immune cells are also known to be osteoclast activating such as RANKL
Diseases due to aberrant bone remodelling
The maintenance of bone homeostasis is dependent on the balance of cellular activities during bone remodelling. Disruption to the balanced regulation of bone remodelling results in a number of disease conditions including osteoporosis, osteopetrosis and Paget's disease of bone.
Conclusion
The process of bone remodelling is tightly coordinated by a myriad of cellular activities. Whilst intimate cross-talk between osteoblasts and osteoclasts is an integral element in bone remodelling, other cells including osteocytes, bone lining cells, osteomacs and endothelial cells of the basic multicellular unit also play an important part. An imbalance of these cellular activities often contributes to bone diseases such as osteoporosis and osteopetrosis or leads to bone growth deformities.
Conflict of interest
No conflict of interest.
Acknowledgements
This work was funded in part by National Health and Medical Research Council of Australia and Sir Charles Gairdner Hospital Research Fund.
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