Effect of age on regulation of human osteoclast differentiation.
Human skeletal aging is characterized as a gradual loss of bone mass due to an excess of bone resorption not balanced by new bone formation. Using human marrow cells, we tested the hypothesis that there is an age-dependent increase in osteoclastogenesis due to intrinsic changes in regulatory factors [macrophage-colony stimulating factor (M-CSF), receptor activator of NF-κB ligand (RANKL), and osteoprotegerin (OPG)] and their receptors [c-fms and RANK]. In bone marrow cells (BMCs), c-fms (r = 0.61, P = 0.006) and RANK expression (r = 0.59, P = 0.008) were increased with age (27-82 years, n = 19). In vitro generation of osteoclasts was increased with age (r = 0.89, P = 0.007). In enriched marrow stromal cells (MSCs), constitutive expression of RANKL was increased with age (r = 0.41, P = 0.049) and expression of OPG was inversely correlated with age (r = -0.43, P = 0.039). Accordingly, there was an age-related increase in RANKL/OPG (r = 0.56, P = 0.005). These data indicate an age-related increase in human osteoclastogenesis that is associated with an intrinsic increase in expression of c-fms and RANK in osteoclast progenitors, and, in the supporting MSCs, an increase in pro-osteoclastogenic RANKL expression and a decrease in anti-osteoclastogenic OPG. These findings support the hypothesis that human marrow cells and their products can contribute to skeletal aging by increasing the generation of bone-resorbing osteoclasts. These findings help to explain underlying molecular mechanisms of progressive bone loss with advancing age in humans.
Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Ping-Lin
PL
Chung
Shuanhu
S
Zhou
Behnam
B
Eslami
Longxiang
L
Shen
Meryl S
MS
LeBoff
Julie
J
Glowacki
D000375:Aging / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis / Q000235:genetics; D053244:Osteoprotegerin / Q000096:biosynthesis; D053245:RANK Ligand / Q000096:biosynthesis / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000096:biosynthesis; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D017154:Stromal Cells / Q000378:metabolism
D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor
AGING; MARROW STROMAL CELL; OPG; OSTEOCLAST; RANKL