Regulation of bone homeostasis: signaling pathways and therapeutic targets

Abstract

As a highly dynamic tissue, bone is continuously rebuilt throughout life. Both bone formation by osteoblasts and bone resorption by osteoclasts constitute bone reconstruction homeostasis. The equilibrium of bone homeostasis is governed by many complicated signaling pathways that weave together to form an intricate network. These pathways coordinate the meticulous processes of bone formation and resorption, ensuring the structural integrity and dynamic vitality of the skeletal system. Dysregulation of the bone homeostatic regulatory signaling network contributes to the development and progression of many skeletal diseases. Significantly, imbalanced bone homeostasis further disrupts the signaling network and triggers a cascade reaction that exacerbates disease progression and engenders a deleterious cycle. Here, we summarize the influence of signaling pathways on bone homeostasis, elucidating the interplay and crosstalk among them. Additionally, we review the mechanisms underpinning bone homeostatic imbalances across diverse disease landscapes, highlighting current and prospective therapeutic targets and clinical drugs. We hope that this review will contribute to a holistic understanding of the signaling pathways and molecular mechanisms sustaining bone homeostasis, which are promising to contribute to further research on bone homeostasis and shed light on the development of targeted drugs.

Keywords: bone cells; bone homeostasis; signal crosstalk; signaling pathway; skeletal disease; therapeutic targets.

FIGURE 1

Biology of osteoblastogenesis and osteoclastogenesis. Osteoblasts originate from BMSCs, maturing through transcription factors like RUNX2 and Osterix. Osteoclasts originate from hematopoietic progenitors that give rise to monocytes and macrophages, which eventually fuse to form the multinucleated cells that resorb bone. The balanced action of these two cell types is vital for skeletal health and ensuring the continuous renewal and repair of bone tissue (created with BioRender.com).

FIGURE 2

RANKL/RANK/OPG signaling system in bone homeostasis. (1) RANKL, produced by osteoblasts, binds to its receptor RANK on osteoclast progenitors, initiating intracellular signaling cascades such as MAPK, NF‐κB, and PI3K/AKT signaling pathway via TRAF6, culminating in the enhancement of NFATc1 expression. (2) RANKL binding with LGR4 suppress NFATc1 by GSK‐3β pathways. (3) Upon binding RANK, RANKL activates the PI3K/AKT/mTOR pathway and promotes nuclear translocation of RUNX2 in osteoblast. (4) OPG is a decoy receptor for RANKL and blocks RANK–RANKL binding (created with BioRender.com).

FIGURE 3

A simplified view of PTH, IGF, and FGF signaling. (1) PTH signaling: PTH activates the PTH1R receptor and then influences intracellular cAMP levels and subsequently engaging PKA and mTOR signaling, with downstream effects on osteoblast activity. (2) IGF‐1 signaling pathway: IGF‐1 signaling can promote the survival and differentiation of osteoblasts through synergistic interactions with PTH or PI3K/AKT/mTOR pathway. IGF‐2 indirectly increases the activity of BMP‐9 and promotes the nuclear translocation of SMAD1/5/8, thereby promoting the osteogenic differentiation of MSCs. (3) FGF signaling pathway: FGF can cross‐regulate the function of osteoblasts through PLCγ, JAK, PI3K, and RAS and regulate the activity of osteoclasts through MAPK pathway. (4) Indirect effect: PTH, IGF, and FGF also can indirectly regulate gene expression in osteoclast via RANK/RANKL (created with BioRender.com).

FIGURE 4

Overview of Wnt, BMP, and TGF‐β signaling pathways. (1) In the active Wnt signaling pathway, Wnt ligands bind to FZD and LRP5/6 receptors, leading to GSK‐3β degradation. β‐catenin enters the nucleus to drive gene transcription and can indirectly regulate the RANKL/RANK and BMP signaling pathways. In the inhibited Wnt signaling pathway, β‐catenin is degraded by protein complexes, resulting in ubiquitin‐mediated proteolysis and no gene transcription. (2) BMP interacts with type II receptors, leading to phosphorylation and activation of R‐SMADs (SMAD1, 5, 8), which then complex with SMAD4 and are cotransported into the nucleus to regulate the expression of osteogenic genes such as RUNX2 and DLX5 in osteoblasts. (3) TGF‐β binds to its receptors, leading to the activation of SMAD2/3, which then associates with Smad4. This complex enters the nucleus and affects the expression of genes that regulate osteoclasts and osteoblasts. (4) In the nonclassical pathway, BMP activates TRAF6/TAK1, triggering MAPK pathways and leading to the phosphorylation of transcription factors like RUNX2, promoting bone formation. TGF‐β can also activate downstream factors like MAPK and PI3K, which regulate transcription factors for bone formation and resorption (created with BioRender.com).

FIGURE 5

A simplified view of Hedgehog, JAK/STAT, AMPK, Notch, NF‐κB, MAPK, and PI3K/AKT pathways. (1) Hedgehog pathway: Hh proteins relieve the inhibitory effect of Ptch on Smo by binding to Ptch on target cells, leading to Smo activation, followed by further activation of Glis and regulation of downstream target genes. (2) JAK/STAT pathway: JAK/STAT pathway is activated by IL‐6, leading to the phosphorylation of STAT3, which then impacts gene expression related to osteoblast activity. (3) AMPK pathway activation through LKB1 phosphorylation inhibits mTORC1 via TSC1/2, affecting osteoblast function. (4) Notch pathway: binding of ligands expressed by neighboring cells to Notch receptors results in the release of NICD from the membrane and translocation to the nucleus, thereby activating transcription of specific genes. (5) NF‐κB pathway: divided into classical and nonclassical branches, shows how different stimuli lead to the activation of distinct NF‐κB subunits, which then translocate to the nucleus influencing both osteoclast and osteoblast gene expression. (6) MAPK pathway: MAPK is activated by various extracellular signals leading to the sequential activation of MAPKKK and MAPKK, further activating downstream molecules such as ERK, JNK, and p38 MAPK. (7) PI3K/AKT pathway: activation of PIP 3 by binding of activated PI3K to PIP2 leads to Akt phosphorylation, linking to NF‐κB and mTOR signaling, pivotal for osteoclast survival and function (created with BioRender.com).

FIGURE 6

Overview of bone homeostasis disorders in skeletal diseases. (1) Osteoporosis: the main types of osteoporosis: postmenopausal osteoporosis and senile osteoporosis. Estrogen withdrawal leads to increased osteoclast activity, and senility decreases osteoblast differentiation and increases lipogenic differentiation. (2) Osteogenesis imperfecta: gene mutations and abnormal signaling pathways lead to impaired osteogenesis and mineralization. (3) Osteoarthritis: the interaction between stress changes and inflammatory environment activates dysfunction in osteoclast and osteoblast. (4) Rheumatoid arthritis: excessive activation of FLS with inflammatory factors is conducive to bone resorption by osteoclasts and impairs bone formation by osteoblasts, which leads to dysregulation of bone homeostasis and joint erosion. (5) Paget's disease of bone: due to the excessive activation of osteoclasts, the bone remodeling cycle is disrupted, resulting in excessive bone resorption and abnormal bone formation. (6) Bone cancer and metastases: bone metastatic cancer cells and osteoclasts enhance each other's activity, exacerbating the “vicious cycle” of bone degradation and tumor growth. (7) Osteonecrosis of the femoral head: it is caused by a variety of factors that affect bone health, such as the impacts of glucocorticoids, the role of the RANKL pathway, and the contributions of osteoclastogenic and osteoblastogenic cytokines. (8) Periprosthetic osteolysis: Ti wear particles will disrupt bone homeostasis by binding to immune cells and altering the activity of osteoblasts and osteoclasts (created with BioRender.com).