Page 117 - Physico-Chemical Niche Conditions for Bone Cells

INTRODUCTION
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 [1], suggesting that (pre) osteoblasts are inherently mechanosensitive. Therefore (pre)osteoblasts still continue to be frequently used to investigate the function of osteogenesis in vitro. Osteogenesis relies strongly on growth factors. A key factor in the regulation is mechanical loading which is transmitted via the extracellular matrix-integrin-cytoskeleton-nucleus system from the matrix all the way to the nucleus [2]. Mitochondria are integral in sensing of mechanical loads to allow the cell to adapt to its environment [3]. They are important in processes such as adenosine triphosphate (ATP) production, calcium homeostasis, and apoptosis [4]. Mitochondrial function is typically under dual genomic control, including nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Most proteins are synthesized from nDNA, while a few enzymes and RNA and tRNA are encoded by mtDNA [5]. Mutations in mitochondria-related nDNA or mtDNA genes give rise to mitochondrial dysfunction [6,7]. Dysfunctional mitochondria have difficulty to produce sufficient ATP to meet energy demand in many tissues or organs, e.g. liver, kidney, endocrine system, nervous system, and skeletal and cardiac muscles [8]. Mitochondrial diseases are profoundly debilitating, such as Wilson’s disease, Freidreich’s Ataxia, the rarer crippling Huntington’s disease, multiple sclerosis, Motoneuron disease, Parkinson’s disease, and Alzheimer’s disease [9–11]. In all of these diseases, the pathophysiological mechanism is still unclear, but there are indications that a relationship exists with mitochondrial dysfunction at some level of the pathogenic process [9]. Notably, the morphology of mitochondria changes tremendously across tissues or organs of varying metabolic needs [12]. The metabolic status can dramatically affect the morphology and function of mitochondria, which consequently results in changes of tissue or organ function [13]. Genetic ablation of important ingredients of mitochondrial fission and fusion result in metabolic changes which have been attributed to perturbations in mitochondrial dynamics [13].
The cytoskeleton, a filamentous protein network structure, is dynamic to provide the cell with resistance to deformation, allows changes in morphology during cell movement and cargo transport. For example, the cytoskeleton connects internal physical and biochemical factors to the external environment, spatially organizes cell contents, and coordinates the cell internal and external forces to move and change shape [14,15]. Physical signaling (internal and external) can be transmitted via the filaments of the cytoskeleton to the other structures or organelles including nucleus, endoplasmic reticulum, golgi apparatus and mitochondria [16,17]. It is remarkable that the network structure of cytoskeletal filaments can exhibit
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