Factors influencing Osteoclasts and Osteoblasts

Hormones are possibly the most crucial modulators of bone formation. It is well established that estrogen, parathyroid hormone, and to a lesser extent testosterone, are essential for optimal bone development and maintenance. Of these, estrogen is now believed to have the most direct effect on bone cells, interacting with specific proteins, or receptors, on the surface of osteoblasts and osteoclasts.

This interaction sets off a complex chain of events within the cells, increasing osteoblast activity while at the same time interfering with osteoblast-osteoclast communication – one of the ironies of bone remodeling is that the osteoblasts release factors that stimulate osteoclasts and drive bone resorption, as we shall see below.

Estrogen effects are mediated through one specific type of cell surface receptor called the estrogen receptor alpha (ERα), which binds and transports the hormone into the nucleus of the cell where the receptor-hormone complex acts as a switch to turn on specific genes. ERα receptors are found on the surface of osteoblasts, as is estrogen receptor-related receptor alpha (ERRα), which may play an auxillary role in regulating bone cells. Recent studies also suggest that sex hormone binding globulin (SHBG), which facilitates entry of estrogen into cells, may also play a supportive role.

Estrogen, of course, is made and secreted into the bloodstream some distance from bone and it also has profound effects on other tissues, such as the uterus and breast. But there are other, locally produced signalling molecules that have profound effects on bone physiology.

Prostaglandins, particularly progtaglandin E2 (PGE2), stimulate both resorption and formation of bone. PGE2 is a lipid that is formed in various bone cells from a precursor called arachidonic acid. The first step on PGE2 synthesis is carried out by an enzyme called cyclooxygenase 2 (COX2) and inhibitors of this enzyme can prevent bone formation in response to mechanical stress in animals. PGE2 may be required for exercise-induced bone formation.

There is evidence that fracture risk is increased in people taking non-steroidal anti-inflammatory drugs that inhibit COX-2 may also increase. Another set of lipid molecules that appear to regulate bone remodeling are the leukotrienes. Also derived from arachidonic acid, these have been found to reduce bone density in mice.

How any of these hormones impact bone remodeling depends on how they alter osteoclasts and/or osteoblasts activity. Recently, scientists have started to uncover specific cell surface receptors that help transmit signals from outside bone cells into the cell nucleus, where different genes that regulate cell activity can be switched on or off. These include receptors for bone morphogenetic proteins (BMPs) a family of proteins which are potent inducers of bone formation.

BMP receptors have been found on the surface of osteoblasts precursor cells. Another cell surface receptor called the low density lipoprotein (LDL)-related protein 5 receptor (LRP5) may also be important for bone formation because loss of LRP5 in animals leads to severe osteoporosis. BMP receptors and LRP5 may cooperate to stimulate osteoblasts into action, though exactly how this might occur has not been clarified.

Scientists have had more success piecing together various components that stimulate osteoclast activity. It was discovered that a cell surface receptor called RANK (for receptor activator of NFkB) prods osteoclasts precursor cells to develop into fully differentiated osteoclasts when RANK is activated by its cognate partner RANK ligand (RANKL).

RANKL, in fact, is produced by osteoblasts and is one of perhaps many signaling molecules that facilitate cross-talk between the osteoblasts and osteoclasts and help coordinate bone remodeling. Osteoprotegerin, another protein released by osteoblasts, can also bind to RANKL, acting as a decoy to prevent RANK and RANKL from coming in contact. The balance of RANKL/osteoprotegerin may be crucial in osteoporosis. In fact, animal studies showed that increased production of osteoprotegerin leads to an increase in bone mass, while loss of the protein leads to osteoporosis and increased fractures. Inhibitors of RANKL have also shown promise as potential treatment for osteoporosis in humans.

A second, complementary cell signalling system that helps drive formation and activation of osteoclasts was also uncovered within the last few years. In the absence of DNAX-activating protein 12 (DAP12) and Fc Receptor common γ chain (FcRγ), two cell surface receptors, mice develop severe osteoporosis – the exact opposite of osteoporosis – characterized by a dramatic increase in bone density. These two cell surface receptors interact with a group of proteins in the cell called ITAM (immunoreceptor tyrosine-based activation motif) adaptor proteins to cause an increase in intracellular calcium.

Studies suggest that the RANK/RANKL and the ITAM-mediated pathways cooperated to induce full osteoclasts activity. These two pathways may converge to activate a protein called the nuclear factor of activated T cells (NFAT) c1. NFATc1 serves as a master switch for bone resorbtion because it turns on the genes that osteoclasts precursor cells need to become fully active osteoclasts.

Subtle differences in the genetic code might explain why one person’s osteoblasts or osteoclasts are more active or responsive to their environment, and it might also lead to the discovery of unknown regulatory mechanisms. Environmental factors can also have an enormous impact on bone physiology.