Bone is composed of a mineralized matrix synthesized by osteoblastic cells
and maintained by osteocytic cells embedded within this calcified environment. This
review of recent literature reveals that regulation of bone formation is influenced by a
complex panoply of secreted factors and cell surface receptors which control
proliferation and differentiation of osteoproprogenitor cells as well as the functional
activity and survival of osteoblastic cells and osteocytes. The osteocyte, the
mechanosensor of bone, plays a prominent regulatory role through its control of
osteoblastic lineage cells and of osteoclastic lineage cells in remodeling of bone in
response to external mechanical forces. This concept is illustrated with specific
examples of local, paracrine and systemic signaling mechanisms mediating the
responses of cells in bone. As an indication of the inherent specificity of intercellular
communication mediated by osteocytes, sclerostin and FGF23, a local and a systemic
effector secreted by osteocytes, respectively, are also used as molecular and functional
biomarkers. Sclerostin expression by osteocytes is inversely related to mechanical
stimulation and sclerostin binds to the Lrp5/6 receptor on osteoblastic cells to inhibit the
Wnt1/β-catenin signaling pathway controlling bone formation. Recent work has also
shown that the viability of osteocytes is influenced by estrogen deficiency since
ovariectomy in sheep increased apoptosis or programmed cell death. The mechanism
whereby osteocytes regulate osteoclastogenesis was recently clarified using
osteopetrotic RANKL null mice. Osteocytes were shown to be the major source for this
required pro-osteoclastogenic factor displaying a greater capacity to support
osteoclastogenesis than osteoblasts or bone stromal cells. Finally, while the proliferative
actions of growth factors and cytokines are well documented, TGF-β appears to also
play a prominent role in the prevention of apoptosis of osteoblastic cells. As illustrated
above, the response of bone cells to a generic signal can lead to stimulation or
suppression of proliferation of osteoprogenitor cells, to increased differentiation of bone
forming osteoblastic cells, or to regulated apoptosis of osteoblasts and/or osteocytes.
Keywords: Osteoblasts, osteocytes, mechanosensors, sclerostin, FGF23,
Wnt/beta-catenin, estrogen deficiency, RANKL null mice, growth factors, PHEX,
BMP2, BMP7, cytokines, apoptosis.