Vitamin D Regulation of Osteoblast Function

Osteoblasts are derived from mesenchymal stromal cell (MSC) progenitors and are only transiently present during periods of active bone formation when their differentiation from MSCs is stimulated. The primary function of osteoblasts is to secrete and mineralize the type I collagen-containing extracellular matrix (ECM) of bone. A fraction of osteoblasts become entrapped in the matrix they secrete as osteocytes, a long-lived component of bone having a lifespan measured in years. Osteocytes do not secrete large amounts of ECM proteins but may participate in the mineralization process, which occurs in bone osteoid distal to the osteoblast layer. Cells of the osteoblast lineage also have a number of regulatory functions including control of bone remodeling, regulation of phosphate homeostasis, energy metabolism, and response to mechanical loads. The vitamin D hormone, 1,25(OH)2D3, affects osteoblast function at multiple levels. It controls remodeling via induction of receptor activator of NF-κ ligand, regulates phosphate homeostasis by increasing fibroblast growth factor 23, may influence energy metabolism through stimulation of osteocalcin (BGLAP), and may enhance the response of bone to mechanical loads via stimulation of mitogen-activated protein kinase signaling. In addition, 1,25(OH)2D3 may stimulate MSC differentiation to the osteoblast lineage and suppress adipocyte formation via stimulation of the Wnt pathway. The recent years have been dominated by large-scale, genome-wide approaches (microarrays, Chip-Seq), which have provided many novel, direct targets of 1,25(OH)2D3. However, when it comes to understanding the physiological function of 1,25(OH)2D3 in osteoblasts, large discrepancies exist between different in vitro and in vivo model systems. Furthermore, gene ablation studies of the vitamin D receptor and/or the 1α-hydroxylase gene generally indicate only subtle direct actions of 1,25(OH)2D3 with most functions being attributed to the vitamin D endocrine system maintaining calcium and phosphate homeostasis through stimulation of intestinal absorption. Further work, particularly carefully controlled genetic studies, will be required to discriminate between direct actions of 1,25(OH)2D3 on osteoblasts and systemic effects on mineral homeostasis.

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