## 4 Physiological Relevance of Vitamin D\({}_{3}\) Effects in Dental MSCs  
The biological effects of vitamin D\({}_{3}\) in dental tissues are multifaceted and associated with bone metabolism, immune response, and antimicrobial peptides' production [104]. Most of the studies on the effect of vitamin D\({}_{3}\) on the dental MSCs support its ability to stimulate osteogenic differentiation and inhibit the inflammatory response (Figure 2). However, the physiological relevance of these effects is not so obvious. Most effects of the biologically active metabolite 1,25(OH)\({}_{2}\)D\({}_{3}\) on the osteogenesis and inflammatory response were observed at concentrations of 10-100 nM, which are about 1000 times higher than its serum levels [35]. [PERSON] et al. showed no effect of 1,25(OH)\({}_{2}\)D\({}_{3}\) on the LPS-induced response in hPDLCs at a concentration of about 0.7 nmol/L (3 ng/mL) [57]. Biological effects of 25(OH)D\({}_{3}\) are observed at concentrations of 10-500 nmol/L [45; 47; 48; 49], which only partially reflect those reported in the blood serum [32; 33]. However, it should be noted that the local concentration of vitamin D\({}_{3}\) metabolites in dental tissues and intercellular space might differ from that observed in serum.  
Local vitamin D\({}_{3}\) metabolism could be involved in the regulation of both bone formation and bone resorption. MSCs are a crucial factor for bone formation in the maxilla and mandible [105]. Most studies describe stimulating effects of vitamin D\({}_{3}\) on the osteogenic differentiation of dental MSCs, which implies its positive impact on bone formation. It should be noted that this effect is usually observed in osteogenic media, which contain several artificial components, including dexamethasone. In the absence of these supplements, no effect of vitamin D\({}_{3}\) on the osteogenesis is observed. Moreover, the mechanisms of osteogenic differentiation in vitro and in vivo are different. Most studies suggest that vitamin D\({}_{3}\) increases RANKL/OPG ratio, which might result in increased osteoclasts and bone resorption. Interestingly, dental MSCs with periodontitis-associated VDR phenotype exhibit higher RANKL production upon the stimulation with 1,25(OH)\({}_{2}\)D\({}_{3}\)[106], which argues the physiological importance of this effect. Vitamin D\({}_{3}\) might also inhibit bone resorption indirectly, for example, through inhibition of IL-6 production by different MSCs. Furthermore, the direct and indirect effects of vitamin D\({}_{3}\) on immune cells might modulate their impact on bone metabolism [107].  
The 1,25(OH)\({}_{2}\)D\({}_{3}\) enhances osteogenic differentiation and production of RANKL and antimicrobial peptides and diminishes inflammatory response and immunomodulatory ability of dental MSCs.  
Local vitamin D\({}_{3}\) metabolism might also be involved in the regulation of local inflammatory processes. Resident dental MSCs play an essential role in the progression of inflammatory diseases, such as periodontal disease and pulpitis [18]. Vitamin D\({}_{3}\) attenuates the response of different dental MSCs to inflammatory stimuli, which underlie its anti-inflammatory role under these conditions. However, besides its anti-inflammatory actions, vitamin D\({}_{3}\) might partially abolish the immunosuppressive effect of dental MSCs towards different immune cells [84; 85]. Thus, vitamin D\({}_{3}\) seems to fine-tune the inflammatory response and functions either anti- or pro-inflammatory, depending on the microenvironment. Besides, the expression and activity of local CYP27B1 in dental MSCs are regulated by IL-1\(\beta\)[49]. Our recent study showed that the responsiveness of hPDLCs to 25(OH)D\({}_{3}\) and 1,25(OH)\({}_{2}\)D\({}_{3}\) is diminished under inflammatory conditions [108]. Summarizing, these observations suggest a reciprocal regulation of local vitamin D\({}_{3}\) metabolism and the inflammatory response.