Page 12 - Physico-Chemical Niche Conditions for Bone Cells

General introduction
GENERAL INTRODUCTION
Bone homeostasis
Bone matrix is continuously resorbed (degraded) by osteoclasts and rebuilt by osteoblasts at approximately 1-2 million microscopic sites in every adult skeleton [1]. Bone resorption carried out by osteoclasts in a newly formed osteon takes around 3 weeks, whereas rebuilding by osteoblasts takes around 3-4 months [1]. In bone, osteoblast differentiation and function are affected by transcription factors (e.g. Cbfa1), growth factors and morphogens (e.g. bone morphogenic proteins, fibroblast growth factors, Wnt), as well as their inhibitors (e.g. sclerostin) [2]. Osteoclast differentiation and function are affected by different molecules, such as (amongst many others) the cell surface receptor RANK (receptor activator of nuclear factor kappa B (NFkB)), RANK ligand (RANKL), cytokines such as macrophage-colony stimulating factor (M-CSF), and osteoprotegerin (OPG; decoy receptor for RANKL) [2]. For healthy adults, bone formation and resorption are balanced, thereby ensuring maintenance of bone strength. The balance between bone formation and resorption is affected by several factors, most notably ageing, hormones, and mechanical stimuli [3,4]. Several diseases are associated with a disbalance in bone formation and resorption, i.e. osteoporosis, Paget’s disease, several types of cancer (e.g. solid tumors, hematopoietic malignancies), and inflammatory diseases (e.g. rheumatoid arthritis) [1]. Overloading around badly designed (oral) implants also affects remodeling, and causes bone loss. However, bone remodeling can also be used, e.g. during distraction osteogenesis of the mandible, or for orthodontic tooth displacement [5]. The disbalance in bone formation and resorption can cause bone loss and fractures, which are painful and need to be prevented. Therefore, it is crucial to maintain the bone remodeling balance.
Physical micro-environment (niche) of bone
The physical micro-environment (niche) of osteocytes and (pre)osteoblasts consists of a dynamic set of biophysical stimuli, e.g. shear, stress, strain, pressure, acceleration, streaming potentials, and fluid flow [6]. Fluid flow takes place in the canalicular system of osteocytes, and works as an amplifier of the mechanical signal. In this regard, it is not surprising that the osteocytes are more responsive to fluid flow than osteoblasts or their precursors. Although (pre)osteoblasts are less responsive to fluid flow than osteocytes, they are still sensitive to mechanical stimuli (e.g. physiological loading, or overloading as occurs in gaps around badly osseo-integrated implants), and mice devoid of osteocytes still form bone in response to mechanical loading [7], suggesting that osteoblasts are inherently mechanosensitive. Therefore (pre)osteoblasts still continue to be frequently used to investigate mechanosensation and mechanotransduction in vitro, also because of availability and ease of
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