Sclerostin and occlusion: A brief review.

In its pursuit of understanding the wonders of human body, mankind has stumbled upon yet another discovery which not only is a key to chest of unanswered queries but also opens a plethora of new possibilities. Till recently the osteocytes were considered latent cells merely entrapped in the matrix of bone. With the discovery of beta-catenin pathway and sclerostin molecule, these cells are now being recognized to perform a multitude of physiological functions which are important to bone function and turnover. Mechanosensor function of osteocytes via sclerostin molecule offers new possibilities in alveolar bone preservation. Sclerostin and its inhibitors have potential in prosthetic, regenerative and preventive therapy in dentistry. Osteocytic pathway of sclerostin release and mechanism of its interaction with occlusion is discussed in this article.

INTRODUCTION

In its pursuit of understanding the wonders of the human body, mankind has stumbled upon yet another discovery, which not only is a key to the chest of unanswered queries, but also opens a plethora of new possibilities. Until recently, the osteocytes were considered latent cells merely entrapped in the matrix of bone. With the discovery of beta-catenin pathway and sclerostin molecule, these cells are now being recognized to perform a multitude of physiological functions that are important to bone function and turnover. Mechanosensor function of osteocytes via sclerostin molecule offers new possibilities in alveolar bone preservation. Sclerostin and its inhibitors have potential in prosthetic, regenerative and preventive therapy in dentistry. Osteocytic pathway of sclerostin release and mechanism of its interaction with occlusion is discussed in this article.

OSTEOCYTES

Some osteoblasts become progressively encased within the matrix they contributed to build and be left behind as the deposition-front progresses, while maintaining their intercellular junctions with the neighboring cells on the surface. As they become trapped within a lacuna in bone these osteoblasts differentiate to a stage known as osteocyte.[1] This complex network of cells with intercellular junction enables the bone to renovate and continuously respond to mechanical and metabolic stimuli. This mechanosensor like function of osteocytes has recently been discovered.[2] Aguirre et al. observed osteocyte apoptosis in the absence of mechanical loading and osteoclast recruitment later.[3] Selective ablation of osteocytes also showed bone osteoporotic changes.[4] Growing recognition of the role of osteocytes lead to the elucidation of gene named SOST encoding a glycoprotein sclerostin.

WNT/BETA-CATENIN SIGNALING

Homeostasis in bone is a tightly-regulated mechanism under control of signaling molecules from various signaling pathways that ultimately controls bone mass and turnover. Among many such pathways, much recent focus has been upon WNT/beta-catenin canonical pathway. WNT/beta-catenin pathway that was once believed to be of importance in embryogenesis is also of importance inter alia in bone formation and turnover.[5]

In this pathway, signaling is primarily mediated through frizzled (Fz) receptors along with co-receptors low density lipoprotein receptor-related protein (LRP5) and LRP6 (-LRP family), which function by regulating the amount of transcriptional co-activator beta-catenin inside the cell. Axin complex (composed of scaffolding protein Axin, Adenomatous polyposis coli gene product, casein kinase-1 and glycogen synthase kinase-3), which continually degrades beta-catenin by its ubiquitation and proteosomal degradation, is deactivated by activation of WNT/beta-catenin pathway receptors. Activation of Fz receptors and co-receptors LRP6 and LRP5 together and subsequent recruitment of scaffolding protein Dishevelled by WNT agonists results in LRP6 phosphorylation and subsequent degradation of Axin complex This degradation of Axin complex results in accumulation of beta-catenin inside cytoplasm that complexes with T-cell factor/lymphoid enhancer factor proteins and travels to nucleus and causes the expression of WNT target gene expression as secretory/proliferatory signals.[6] Thus, LRP5/LRP6 activity correlates with bone mass likely via regulation of osteoblasts proliferation, whereas SOST that is specifically expressed in osteocytes, negatively regulates bone mass by antagonizing LRP5 by sclerostin molecule. Binding of sclerostin, a product of SOST gene to LRP5/LRP6 is inhibitory to WNT/beta-catenin pathway as shown in Figure 1.

Figure 1

Normal WNT/beta-catenin pathways and inhibitory effect of sclerostin through co-receptors low density lipoprotein receptor-related protein (LRP5), LRP6

MECHANICAL UNLOADING AND SCLEROSTIN RELEASE

Mechanosensor function of osteocytes is complex and not completely understood yet. There could be many different sensing organs including primary cilia, cell membrane and dendritic processes etc., or a combination of above.[7] Given their linear and ordered arrangement throughout the bone along with their flawless connectivity with surrounding cells and osteoblasts via gap junctions and hemichannels, osteocytic cells are aptly suited to respond to mechanical stimuli and signal transmission.[8] Upon mechanical stimulation/recognition of mechanical strain these cells show intracellular biochemical changes as in ATP release, nitric oxide and prostaglandin generation. Similarly, mechanical stimulation influences osteocytic expression of SOST gene.[9]

Sclerostin a product of SOST gene, found in osteocytes is capable of inhibit WNT/beta-catenin pathway by binding to LRP5. It has been found that in the absence of mechanical loading antagonizing effect on sclerostin on WNT/canonical pathway in osteoblasts is induced[10] as shown in Figure 2. Sclerostin levels are also increased in menopausal women and elderly and in long term immobilized patients.[11] Furthermore, Inhibition of sclerostin function has led to a successful increase in bone mass in animal models.[12] Antisclerostin antibodies utility in osteoporosis treatment in under research.[13] These antibodies are capable of specifically target binding of sclerostin to LRP5 and LRP6 and prevent sclerostin mediated inhibition of WNT signaling. This action of antisclerostin antibodies would result in osteoblasts differentiation[14] and prevention of apoptotic response in osteocytes and osteoblasts and could be useful in bone anabolic disorders.

Figure 2

Effects of mechanical unloading on osteocytes and resultant effect on osteoblasts by inhibition of WNT/beta-catenin pathway

SCLEROSTIN AND OCCLUSION: DENTIST'S PERSPECTIVE

Every dentist recognizes the importance of mechanical loading to the alveolar bone. Loss of mechanical stimulation to the bone leads to decrease in bone metabolism and leads to ridge resorption.[15] Importance of occlusal loading in implants is already proved.[16] A tooth out of occlusion is shows periodontal and bone density changes. Preservation of the edentulous ridge by antagonizing sclerostin might preserve alveolar bone for denture fabrication. In orthodontics as well, sclerostin might help in gaining newer insights about bone response to mechanical forces.

PERIODONTIST'S PERSPECTIVE

Osteoporosis is considered as a risk factor for periodontitis. Loss of alveolar bone density can be prevented with antisclerostin antibodies as shown in animal models. Apart from this, effect of physiological and traumatic occlusion and its contribution to the periodontium in health and disease would now be understood with sclerostin in equation. This would result in newer insights about both the disease and management. Alveolar bone might be preserved by antisclerostin antibodies that can later be harvested for bone grafting purposing be periodontist.

CONCLUSION

Mechanical unloading induced bone loss is a clear analogy to dental scenario of alveolar ridge resorption, as a result, of tooth loss postextraction. Although still in the research, prospect of developing antisclerostin antibodies might have direct potential utility in dentistry. Further investigation of this molecule, particularly suiting to dental perspective and demands is the need of the hour. Sclerostin is yet to shed light upon many things, and the future use of this molecule in dentistry seems a bright prospect.