Mechanical regulation of bone remodeling

Abstract

Bone remodeling is a lifelong process that gives rise to a mature, dynamic bone structure via a balance between bone formation by osteoblasts and resorption by osteoclasts. These opposite processes allow the accommodation of bones to dynamic mechanical forces, altering bone mass in response to changing conditions. Mechanical forces are indispensable for bone homeostasis; skeletal formation, resorption, and adaptation are dependent on mechanical signals, and loss of mechanical stimulation can therefore significantly weaken the bone structure, causing disuse osteoporosis and increasing the risk of fracture. The exact mechanisms by which the body senses and transduces mechanical forces to regulate bone remodeling have long been an active area of study among researchers and clinicians. Such research will lead to a deeper understanding of bone disorders and identify new strategies for skeletal rejuvenation. Here, we will discuss the mechanical properties, mechanosensitive cell populations, and mechanotransducive signaling pathways of the skeletal system.

Fig. 1

The structural basis of mechanical stress in skeletal cells. a The skeletal system contains osteoblasts, osteoclasts, osteocytes, and their progenitors, all sensitive to mechanical stimuli. Osteocytes are the most common mechanical sensors among these cells due to their structure and location in the bone matrix. Mesenchymal stem cells and osteoblast progenitors can sense the FSS in the bone marrow cavity and the strain on the bone. Osteoclasts are both mechanosensitive cells and the effectors for other mechanosensitive cells. b. The mechanical stimuli placed on bone may include shear stress, hydrostatic pressure, mechanical stretch and tension, matrix stiffness, and matrix alignment.

Fig. 2

Forces and cellular structures involved in mechanosensation. Mechanical stresses of varying type and intensity are sensed by different families of cellular structures, including integrins, receptors, ion channels, connexins, and cilia.

Fig. 3

Specific mechanosensitive structures. a Focal adhesions. Focal adhesions connect ECM mechanical signals to the cytoskeleton, affecting cytoskeletal arrangement and crosslinking. b Cilium. Cilia usually coordinate with the Hedgehog (Hh) signaling pathway to transmit mechanical signals. c GPCRs. GPCRs containing a C-terminal helix 8 can sense mechanical stimuli. Activation of the GPCR initiates a series of signal transductions, including the Rho-Rock and PLC-IP3 pathways. d Ion channels. Activation of ion channels by mechanical stimuli elicits specific ion flow, especially calcium influx, to modulate downstream signaling pathways.

Fig. 4

Mechanotransduction signaling pathways. a Wnt signaling pathway under mechanical loading and unloading conditions. Unloading can increase the expression of Sost and repress the expression of Postn, thus inhibiting osteogenic gene expression, while loading has the opposite effect. Wnt and RhoA/Rock/cytoskeleton have synergetic effects in the process of mechanotransduction. b MSCs favor a commitment to osteoblasts in the rigid matrix and adipocytes in the soft matrix. Several signaling pathways are involved in this lineage commitment, including cytoskeleton rearrangement, YAP/TAZ nuclear translocation, and BMP2/Smad activation.