Osteoclast Commitment, Differentiation, and Function

Based on a contribution by Dr. Marla Steinbeck, Orthopedic Research Laboratory, Thomas Jefferson Medical School, Philadelphia, PA.

Osteoclasts are derived from hematopoietic stem cells (CFU-GM) and share phenotypic characteristics with circulating monocytes and tissue macrophages (Kurihara et al., 1990; Hattersley et al., 1991).

The PU.1 transcription factor and osteocyte commitment

Osteoclasts are formed from a population of the circulating mononuclear cells that are recruited from the blood to the bone surface where they undergo differentiation and fusion to form multinucleated cells. The PU.1 transcription factor increases as macrophages assume an osteoclastic phenotype. Factors that induce the formation of osteoclasts (dexamethasone, 1, 25-dihydroxyvitamin D3) also cause the increase in PU.1. Mice born with homozygous deficiency of the PU.1 genes lack both macrophages and osteoclasts. They die (of infection due to the lack of macrophages) shortly after birth, and autopsies shows that their bones have an osteopetrotic phenotype.

Osteopetrosis is a family of diseases characterized by the failure of the long bones to be remodeled. The resulting long bones have cartilagenous infiltration towards the center of the bone from the growth plate and a poorly remodeled center. While osteoporosis can be caused by too many osteoclasts, osteopetrosis can be caused by not having sufficient numbers of these cells. Tondravi and colleagues (1997) have shown that one form of mouse osteopetrosis can be caused by genetic deficiency of a transcription factor that is needed for osteoclast differentiation.

Osteoblast-derived factors ODF and M-CSF in osteoclast differentiation on the bone matrix

The presence of stromal cells or pre-osteoblasts within the bone microenvironment appears to be essential for the differentiation and subsequent functional activation of these cells. These cells respond to osteotrophic factors such as Vitamin D₃, parathyroid hormone (PTH), and parathyroid hormone related protein (PTHrP) and are responsible for the production of M-CSF (macrophage colony stimulating factor) and ODF (osteoclast differentiation factor), factors that play direct roles in osteoclast proliferation, survival, and differentiation (Figure 1; Matsuzaki et al., 1998; Tsukii et al., 1998). Thus, the osteoblast precursors help the differentiation of the osteoclasts, as well. Other factors such as interleukin 6 and 11 (IL-6, IL-11) and oncostatin M are also produced in response to Vitamin D₃ and PTH, but their role is to modulate osteoblast function. The binding of ODF to its receptor on the osteoclast leads to the activation of the transcription factor NF-kB, which is involved in increasing the expression of genes that play a role in the differentiation and/or function of the osteoclast. The expression of other important transcription factors involved in osteoclast differentiation include at least one of the c-Fos family members and Mitf (microphthalmia).

Figure 1   Pathway for osteoclast differentiation. The first step involves the formation of the pre-osteoclast. Here, the transcription factor PU.1 is essential. The second step involves converting the mononucleated pre-osteoclast to an active multinucleated osteoclast. This invoves two factors produced by pre-osteoblasts. The first factor is M-CSF; the second factor is ODF. M-CSF allows the c-fos and Mi transcription factors to become expressed, and ODF signaling activates NF-kB. Together, these transcription factors activate the genes critical for converting the pre-osteoclast into an osteoclast. (Drawn by M. Steinbeck, 2000.)

Osteoclasts in aging and disease

Loss of ovarian function following menopause often results in a progressive loss of trabecular bone mass and eventually to osteoporosis. This bone loss is in part due to the increased production of osteoclasts. This increased production of osteoclasts appears to be due to the increased elaboration by support cells of osteoclastogenic cytokines such as IL-1, tumor necrosis factor, and IL-6, all of which are negatively regulated by estrogens. Shevde and colleagues (2000) have shown that estrogen negatively regulates NF-kB and M-CSF-induced differentiation of mononuclear precursors into multinucleated osteoclasts. Estrogen blocks the transcription of M-CSF-induced proteins and, by downregulating the expression of osteoclastogenic cytokines, forms osteoblasts.