Journal de la nanomédecine et de la découverte biothérapeutique
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Osteocyte-specific Cas knockout mice exhibit decreased bone mass through increased osteoclastic bone resorption Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Japa

Tsuyoshi Miyazaki

The skeleton could be a metabolically active organ that undergoes continuous remodeling throughout life. Osteoporosis, which is fostered by advancing age, is that the most typical clinical disorder affecting bones. Although it's been postulated that osteocytes play a crucial role in sensing mechanical load in bone tissues, detailed molecular mechanisms of how osteocytes regulate bone metabolism remain largely unclear. The adaptor molecule p130Cas (Crk-associated substrate, hereafter stated as Cas), which is phosphorylated at focal adhesions upon extracellular matrix engagement, is involved in various cellular processes including migration, survival, transformation, and invasion. additionally, we reported that Cas binds to the cytoskeletons in an exceedingly stretch-dependent manner. this means that Cas can function as an initiator of intracellular signaling cascades through forcedependent changes within the cytoskeleton network. to research the role of Cas in bone metabolism, we generated osteocyte-specific Cas conditional knockout (cKO) mice by mating Casflox/flox mice with Dentin matrix protein 1 (Dmp1)-Cre transgenic mice, within which the Cre recombinase gene was specifically expressed in osteocytes. The resulting Dmp1Cre+/–; Casflox/flox mice (referred to herein as Cas cKO mice) exhibited a big decrease in bone volume, as determined by µCT analysis. Histomorphometric analysis of Cas cKO mice revealed a big increase within the eroded surface/bone surface ratio, osteoclast surface, and osteoclast number. Furthermore, the expression levels of RANKL genes were significantly increased within the osteocyte fractions derived from Cas cKO mice. Collectively, these findings suggest that the bone loss in Cas cKO mice was caused by increased osteoclatstic bone resorption. Under physiologic conditions, interactions between cells present within the bone remodeling compartment (BRC) lead to a balanced and matched remodeling of bone, a lifelong process to blame for bone damage repair and mineral homeostasis. one in all the functions of the osteocyte network is to detect microdamage and trigger its repair ; consequently, osteocytes have a prominent role within the initiation of bone remodeling at selected sites of the skeleton. Increased osteocyte apoptosis has been shown to be induced in vivo in areas of microdamage in several pathological conditions related to enhanced bone resorption like overload, bone disuse, glucocorticoid administration or estrogen deficiency suggesting that apoptosis is linked to targeted bone resorption