Bone Cell Mechanoresponsiveness - Skeletal Aging and Osteoporosis: Biomechanics and Mechanobiology - page 181

5 Humoral and Paracrine Factors in Mechanotransduction
Just as estrogen plays a permissive or synergistic role in bone cell mechano-
transduction, so also do humoral and paracrine factors; two of these, parathyroid
hormone (PTH) and insulin-like growth factors (IGFs), reveal age-related effects
in bone cell mechanoresponsiveness.
PTH plays diverse roles in skeletal adaptation. Intermittent doses of PTH(1-34)
stimulate bone formation [ 32 ], whereas continuous administration promotes bone
resorption [ 71 ]. PTH treatment synergizes with mechanical loading to enhance
bone formation [ 55 ] and is required for load-induced bone formation, perhaps by
sensitizing either the strain-sensing mechanism itself or early responses of bone to
strain-generated signals [ 21 ]. Donahue et al. have shown that osteoblastic cells
from aged rodents (24-28 mos.) demonstrate an impaired cAMP response to PTH
compared to osteoblastic cells isolated from young (4 mo.) rats, suggesting an age-
related decrease in G protein signaling in osteoblastic cells [ 22 ].
IGFs are anabolic agents within bone, where they function to increase cell
number and decrease apoptosis in osteoprogenitors, and stimulate osteoblast
recruitment to the bone surface [ 46 ]. Like PTH, IGF synergizes with mechanical
loading [ 97 ], and bone cell responsiveness to IGF decreases with age [ 52 , 83 ]
through decreased IGF-IR signaling [ 17 ].
6 Attenuated Response to Loading in the Aged May be Due
to Fewer Mechanosensory Cells
All osteogenic cell types within the skeleton—the MSC, the osteoblast, the bone-
lining cell, and the osteocyte—are mechanoresponsive. Because the evidence
examined above does not suggest a diminished capacity of these cells to respond to
load, one can consider the alternate hypothesis that there are simply fewer of these
cells present within the skeleton to respond to load. MSC frequency within the
bone marrow compartment is on the order of 1 per 10 5 stromal cell in younger
individuals [ 74 ], and this declines with age [ 65 , 76 ], in part due to reduced
plasticity of MSCs and a concomitant shift toward an adipocytic phenotype [ 105 ].
Such reductions in MSC frequency, and general phenotypic drift towards an
adipocyte, would decrease the number of osteoblasts capable of perceiving
mechanical loads on their own, or biochemical signals from responding osteocytes.
Osteocytes are considered the most important mechanosensor within bone: they
are present uniformly throughout bone, they are the most abundant cell type within
bone (ten fold greater number than osteoblasts [ 72 ]), and their dendritic processes
allow for direct cell-cell communication to neighboring osteocytes, osteoblasts,
and mesenchymal stem cells. Indeed, osteocyte ablation prevented disuse-induced