Current perspectives on the multiple roles of osteoclasts: Mechanisms of osteoclast-osteoblast communication and potential clinical implications

Abstract

Bone remodeling is a complex process involving the coordinated actions of osteoblasts and osteoclasts to maintain bone homeostasis. While the influence of osteoblasts on osteoclast differentiation is well established, the reciprocal regulation of osteoblasts by osteoclasts has long remained enigmatic. In the past few years, a fascinating new role for osteoclasts has been unveiled in promoting bone formation and facilitating osteoblast migration to the remodeling sites through a number of different mechanisms, including the release of factors from the bone matrix following bone resorption and direct cell-cell interactions. Additionally, considerable evidence has shown that osteoclasts can secrete coupling factors known as clastokines, emphasizing the crucial role of these cells in maintaining bone homeostasis. Due to their osteoprotective function, clastokines hold great promise as potential therapeutic targets for bone diseases. However, despite long-standing work to uncover new clastokines and their effect in vivo, more substantial efforts are still required to decipher the mechanisms and pathways behind their activity in order to translate them into therapies. This comprehensive review provides insights into our evolving understanding of the osteoclast function, highlights the significance of clastokines in bone remodeling, and explores their potential as treatments for bone diseases suggesting future directions for the field.

Keywords: bone homeostasis; clastokines; communication; coupling; medicine; osteoblasts; osteoclasts.

Figure 1.. Matrix-derived coupling factors.

To carry out their bone resorptive activity, mature osteoclasts secrete serine proteases, MMPs, ADAMs, and BMPs that cleave latency-associated proteins and liberate coupling factors from the extracellular matrix (ECM). TGF-β1 and IGF-1 are the two major factors that are released from the ECM following osteoclast bone resorption. TGF-β1, released after cleavage of LTBP by osteoclast-secreted proteases, acts on osteoblast precursors by activating SMAD signaling to promote cell migration, and on osteoclasts to stimulate the production of WNT10B and CXCL16. WNT10B stimulates osteoblast differentiation and mineralization, while CXCL16 collaborates with TGF-β to enhance osteoblast precursor migration to the resorptive sites. IGF-1 is activated after cleavage of its regulatory protein IGFBP by proteases secreted by osteoblasts upon bone resorption. Active IGF-1 induces differentiation of osteoblast precursors recruited by TGF-β1 by activating the mammalian target of rapamycin(mTOR) signaling pathway. BMP-1: bone morphogenetic protein 1; CXCL16: C-X-C motif chemokine ligand 16; IGF-1: insulin-like growth factor 1; IGFBP: insulin-like growth factor-binding protein; LTBP: latent TGF-β-binding protein; MMPs: metalloproteinases; TGF-β1: transforming growth factor-β1.

Figure 2.. Schematic representation of clastokines produced by osteoclasts and osteoclast precursors and interaction with their receptors on cells from the osteoblast lineage.

The picture shows the pathways that were demonstrated to carry out clastokine anabolic function in vivo and their known interactions. However, many mechanisms and molecular players remain poorly understood.

Figure 3.. Schematic summary of potential applications of clastokines for treatment and diagnosis of bone diseases based on research evidence.

Clastokines may be used as anabolic drugs able to promote bone formation without negatively affecting bone resorption. RANKL represents a target for pharmacological inhibition to activate reverse signaling and promote bone formation while simultaneously suppressing bone resorption. Circulating levels of clastokines correlate with bone quality in human, implying the possibility of using them as predictive biomarkers. Clastokines such as cardiotrophin-1 (CT-1) and leukemia inhibitory factor (LIF) have been shown to inhibit sclerostin production by osteocytes and have the potential to be used as sclerostin inhibitors with limited side effects. Titanium osteoimplants have been demonstrated to modulate osteoclast secretory phenotype, increasing clastokine production and promoting a bone healing environment.

Figure 4.. Timely activation of clastokines during bone remodeling.

Bone remodeling is generally classified into three phases: initiation, transition, and termination. During the initiation phase, preosteoclasts are recruited to the bone remodeling site. These cells have been demonstrated to secrete C3a and PDGF-BB clastokines, but also soluble SEMA4D, which has an inhibitory effect on osteoblast differentiation. In the transition phase, mature, bone resorptive osteoclasts promote switching toward bone formation in three ways: by releasing coupling factors from the matrix, by directly secreting them, and by engaging in direct cell–cell contact with cells of the osteoblast lineage. They are also able to release extracellular vesicles (EVs) containing stimulatory and inhibitory miRNAs or vesicular RANK, activating RANKL reverse signaling. Apoptotic osteoclasts have been shown to also release vesicular RANK, which could further stimulate osteoblast differentiation during the termination phase. Putative clastokines are listed in italic.