Retinoid receptors in bone and their role in bone remodeling

Abstract

Vitamin A (retinol) is a necessary and important constituent of the body which is provided by food intake of retinyl esters and carotenoids. Vitamin A is known best for being important for vision, but in addition to the eye, vitamin A is necessary in numerous other organs in the body, including the skeleton. Vitamin A is converted to an active compound, all-trans-retinoic acid (ATRA), which is responsible for most of its biological actions. ATRA binds to intracellular nuclear receptors called retinoic acid receptors (RARα, RARβ, RARγ). RARs and closely related retinoid X receptors (RXRα, RXRβ, RXRγ) form heterodimers which bind to DNA and function as ligand-activated transcription factors. It has been known for many years that hypervitaminosis A promotes skeleton fragility by increasing osteoclast formation and decreasing cortical bone mass. Some epidemiological studies have suggested that increased intake of vitamin A and increased serum levels of retinoids may decrease bone mineral density and increase fracture rate, but the literature on this is not conclusive. The current review summarizes how vitamin A is taken up by the intestine, metabolized, stored in the liver, and processed to ATRA. ATRA's effects on formation and activity of osteoclasts and osteoblasts are outlined, and a summary of clinical data pertaining to vitamin A and bone is presented.

Keywords: osteoblast; osteoclast; osteoporosis; retinoids; vitamin A.

Figure 1

Vitamin A is provided from the food either as preformed vitamin A (retinyl esters) or as provitamin A carotenoids. Retinyl esters are hydrolyzed by pancreatic and intestinal enzymes and free retinol is taken up by the enterocytes. Half of the carotenoids is oxidized to retinal and then reduced to retinol. Retinol is esterified with long-chain fatty acids and incorporated into chylomicrons together with intact carotenoids and then carried by the lymphatics. The chylomicrons are taken up by hepatocytes in the liver where vitamin A is stored as retinyl esters. Before being released from the liver to the circulation, retinyl esters are hydrolyzed to retinol which binds to retinol-binding protein (RBP).

Figure 2

Retinoids reach target cells mainly in the form of retinol bound to RBP. A fraction of retinoids is also delivered by chylomicrons. Inside the cell, retinol is oxidized to the active metabolite ATRA by ADH and RALDH via all-trans-retinal that is bound by CRBP. ATRA is shuttled to the nucleus by CRABP and FABP, facilitating binding to RARs and PPARs, respectively. RARs and PPARs form heterodimers with RXRs to activate transcription. In addition, ATRA can bind to RORs to initiate transcription. Non-genomic effects of retinoids include phosphorylation of CREB that translocates to the nucleus and activates genes. ATRA is inactivated by oxidation by CYP26 enzymes.

Figure 3

Regulation of osteoclast formation in cortical (A) and trabecular (B) bone. At the periosteal site of cortical bone [(A), left], ATRA stimulates RANKL production in osteoblasts and/or osteocytes which leads to stimulation of differentiation of mature osteoclasts from osteoclast progenitors. Unlike in bone marrow, ATRA does not inhibit differentiation of these osteoclast progenitors. In bone marrow or at endosteal site [(A), right], ATRA does not stimulate RANKL formation but inhibits differentiation of osteoclast progenitors to mature osteoclasts. The role of ATRA for osteoclast formation on the endosteal surfaces of trabecular bone (B) is currently not known.

Figure 4

Regulation of bone formation by ATRA. In rats, ATRA inhibits bone formation in cortical bone (left). In cell cultures, ATRA seems to inhibit osteoblast differentiation at low concentrations and to stimulate at high concentrations (right). In addition, ATRA may stimulate differentiation of osteoblasts to osteocytes.