Molecular Basis of Bone Aging

Abstract

A decline in bone mass leading to an increased fracture risk is a common feature of age-related bone changes. The mechanisms underlying bone senescence are very complex and implicate systemic and local factors and are the result of the combination of several changes occurring at the cellular, tissue and structural levels; they include alterations of bone cell differentiation and activity, oxidative stress, genetic damage and the altered responses of bone cells to various biological signals and to mechanical loading. The molecular mechanisms responsible for these changes remain greatly unclear and many data derived from in vitro or animal studies appear to be conflicting and heterogeneous, probably due to the different experimental approaches; nevertheless, understanding the main physio-pathological processes that cause bone senescence is essential for the development of new potential therapeutic options for treating age-related bone loss. This article reviews the current knowledge concerning the molecular mechanisms underlying the pathogenesis of age-related bone changes.

Keywords: bone aging; bone loss; osteoporosis; senescence.

Figure 1

Bone changes leading to senile osteoporotic bone. With aging an imbalance in bone remodeling phases is observed with an increased bone resorption (initiated by osteoclasts) and a decrease in bone formation (carried out by osteoblasts). This imbalance leads to both trabecular and cortical alterations: the reduction of the trabecular number, the decreased trabecular thickness and the increased trabecular spacing; the cortical thinning and the expansion of bone marrow cavity. ↑: increased; ↓: decreased.

Figure 2

Bone cells differ0entiation. The differentiation of bone marrow stem cells (BMSCs) into osteoblasts is led by transcription factors Runt-related transcription factor 2 (Runx2), Osterix and is enhanced by Wnt, which in turn inhibits adipogenesis. The recruitment, differentiation and activity of osteoclasts are mainly regulated by the Receptor Activator of NF-κB (RANK)/RANK ligand (RANK-L)/osteoprotegerin (OPG) system and by macrophage-colony stimulating factor (M-CSF). OPG is the decoy receptor of RANK-L that strongly inhibits osteoclast formation and activity. Osteocytes are involved in the regulation of bone metabolic activities via the production of several factors. HSCs: hematopoietic stem cells; FOXP: forkhead transcription factor P; BMPs: bone morphogenic proteins; Dkk-1: Dickkopf-1; C/EBPα: CCAAT-enhancer binding protein α; PPARγ: peroxisome proliferator-activated receptor γ; NO: nitric oxide; PGE2: prostaglandin E2.