Osteocyte Network; a Negative Regulatory System for Bone Mass Augmented by the Induction of Rankl in Osteoblasts and Sost in Osteocytes at Unloading

Abstract

Reduced mechanical stress is a major cause of osteoporosis in the elderly, and the osteocyte network, which comprises a communication system through processes and canaliculi throughout bone, is thought to be a mechanosensor and mechanotransduction system; however, the functions of osteocytes are still controversial and remain to be clarified. Unexpectedly, we found that overexpression of BCL2 in osteoblasts eventually caused osteocyte apoptosis. Osteoblast and osteoclast differentiation were unaffected by BCL2 transgene in vitro. However, the cortical bone mass increased due to enhanced osteoblast function and suppressed osteoclastogenesis at 4 months of age, when the frequency of TUNEL-positive lacunae reached 75%. In the unloaded condition, the trabecular bone mass decreased in both wild-type and BCL2 transgenic mice at 6 weeks of age, while it decreased due to impaired osteoblast function and enhanced osteoclastogenesis in wild-type mice but not in BCL2 transgenic mice at 4 months of age. Rankl and Opg were highly expressed in osteocytes, but Rankl expression in osteoblasts but not in osteocytes was increased at unloading in wild-type mice but not in BCL2 transgenic mice at 4 months of age. Sost was locally induced at unloading in wild-type mice but not in BCL2 transgenic mice, and the dissemination of Sost was severely interrupted in BCL2 transgenic mice, showing the severely impaired osteocyte network. These findings indicate that the osteocyte network is required for the upregulation of Rankl in osteoblasts and Sost in osteocytes in the unloaded condition. These findings suggest that the osteocyte network negatively regulate bone mass by inhibiting osteoblast function and activating osteoclastogenesis, and these functions are augmented in the unloaded condition at least partly through the upregulation of Rankl expression in osteoblasts and that of Sost in osteocytes, although it cannot be excluded that low BCL2 transgene expression in osteoblasts contributed to the enhanced osteoblast function.

Genetic Studies of Endophenotypes From Spine CT Scans Provide Novel Insights Into the Contribution of Mechanosensory Pathways to Vertebral Fractures and Spinal Curvature

“…Subsequently glutamate signalling has been identified as a key signalling pathway potentially regulating bone responses to mechanical loading (30) . Of the other 5 loci Nielson et al identified as being associated with vBMD, WNT4 is also reported to be mechanosensitive, being upregulated within the developing joint line in embryonic mice lacking skeletal muscle (31) , osteoprotegerin(OPG) (coded for by TNFRSF11B) expression is reduced by mechanical loading in osteoblasts in mice (32) , and TNFSF11/RANKL expression in osteoblasts is reportedly increased by unloading (33) . The suggestion that genetic variation in genes involved in skeletal responses to mechanical loading contribute to lumbar spine vBMD, complements findings presented by Yau et al implying that muscle loading, via paraspinal muscle function, contributes to spinal curvature (see Figure 1).…”

Instructive composites for bone regeneration

“…[32][33][34][35] It is hypothesized that such external stimuli induce interstitial fluid flow along the canaliculi, and consequently provoke shear stresses that deform the osteocyte membrane. [36,37] In response to these stimuli, osteocytes modulate the secretion of many molecules, e.g. insulin-like growth factors (IGF), osteocalcin, sclerostin, nitric oxide, RANKL, TNF-related cytokines and osteoclasts differentiation factors (ODF).…”

“…[34][35][36][37] Through this process, osteocytes allow bone tissue adapting to external mechanical stresses by inducing osteoblasts to synthesize new bone matrix when there are increased loads, or inducing osteoclasts resorbing tissue when there is a decreased use of the bone. [34][35][36][37] Other physical triggers for remodeling are the micro-cracks that form in bone tissue due to continuous stresses during life. [137,138] In such scenario, osteocyte apoptosis occurs in proximity of the cracks.…”

“…water), its chains can move to reach an energetic equilibrium in the liquid-polymer contact eventually allowing more or less fluid penetration. [36,37] The monomer type influences on the polymer crystallinity. Particularly, polylactide having high D,L-lactide content is more amorphous.…”

“…It is proposed that the extra-cellular fluid (i.e. ECF) component of body fluids is an important actor in such instructing system [34][35][36][37][96][97][98] and participate in many phenomena including tissue regeneration and foreign body and inflammatory reactions. [95,96] Cells can bind to specific molecules (i.e.…”