Physiological Bone Remodeling: Systemic Regulation and Growth Factor Involvement

Abstract

Bone remodeling is essential for adult bone homeostasis. It comprises two phases: bone formation and resorption. The balance between the two phases is crucial for sustaining bone mass and systemic mineral homeostasis. This review highlights recent work on physiological bone remodeling and discusses our knowledge of how systemic and growth factors regulate this process.

FIGURE 1.

Physiological bone remodeling Bone remodeling follows coordination of distinct and sequential phases of the process. The remodeling cycle is composed of six sequential phases, namely, quiescence, activation, resorption, reversal, formation, and termination. Activation precedes resorption, which precedes reversal, with mineralization as the last step. The first stage of bone remodeling involves detection of an initiating remodeling signal, which has usually been described as resorption by osteoclasts. In the resorption phase, osteoblasts respond to signals generated by osteocytes or direct endocrine activation signals, recruiting osteoclast precursors to the remodeling site. The resorption phase is of limited duration depending on level of the stimuli responsible for osteoclast differentiation and activity. It is followed by the reversal phase that is characterized by disappearance of almost all osteoclasts. The formation phase is distinct by complete replacement of osteoclastic cells with osteoblastic cells. The termination signals of bone remodeling include the terminal differentiation of the osteoblast. The resting bone surface environment is maintained until the next wave of remodeling is initiated.

FIGURE 2.

Systemic and growth factor regulation of bone remodeling PTH induces differentiation of committed osteoblast precursors, induces RUNX2 expression in osteoblasts, increases osteoblast numbers, and extends osteoblast survival. PTH stimulates the proliferation and differentiation of osteoprogenitors to mature osteoblasts via IGF-1. Along with IGF-I, PTH induces RANKL and MCSF from mature osteoblasts to promote osteoclastogenesis. PTH elevates cAMP levels and inhibits Mef2-stimulated Sost promoter activity, leading to decreased expression of sclerostin and an elevated bone formation rate. 1,25(OH)₂D₃ stimulates osteoblastogenesis via differentiation of mesenchymal stem cells (MSCs) to osteoblasts. Calcitonin increases osteoblast proliferation and suppresses bone resorption by inhibiting the activity of osteoclasts. Estrogen inhibits bone resorption by directly inducing apoptosis of the bone-resorbing osteoclasts. Androgens can also indirectly inhibit osteoclast activity and bone resorption via effects on osteoblasts/osteocytes and the RANKL/RANK/OPG system. Besides systemic hormonal regulation, other growth factors, such as IGFs, TGF-β, FGFs, EGF, WNTs, and BMPs, also play a significant role in regulation of physiological bone remodeling.