Can losing a communication protein in bone cells change both bone breakdown and bone formation?

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Connexin 43 (Cx43) helps osteocytes communicate with other cells and with their extracellular surroundings. It also regulates signaling and gene expression in osteoblastic cells.

In an experimental study, researchers examined mice lacking Cx43 in osteoblasts/osteocytes or only in osteocytes, with the latter called Cx43(ΔOt) mice. These mice had increased osteocyte apoptosis (programmed cell death), endocortical resorption (bone breakdown along the inner cortical surface), and periosteal bone formation (bone formation on the outer surface). This resulted in larger marrow cavity and total tissue areas measured at the middle of the femoral shaft.

Blocking bone resorption reversed the increase in marrow cavity area but not the increase in total tissue area. This demonstrated that endocortical resorption and periosteal apposition—the addition of bone at the outer surface—are independently regulated.

The researchers anatomically mapped apoptotic osteocytes, protein expression in osteocytes, and bone resorption and formation. The mapping suggested that Cx43 controls osteoclast and osteoblast activity by regulating osteoprotegerin and sclerostin levels, respectively, in osteocytes located in specific areas of cortical bone.

In Cx43(ΔOt) mice, empty lacunae—the small spaces that house osteocytes—and living osteocytes lacking osteoprotegerin were distributed throughout cortical bone. In contrast, apoptotic osteocytes were preferentially located in areas containing osteoclasts. This suggested that osteoclast recruitment requires active signaling from dying osteocytes.

The researchers also deleted Cx43 in cultured osteocytic cells. This increased apoptosis and decreased osteoprotegerin expression.

The authors concluded that Cx43 is essential, in a cell-autonomous manner both in vivo and in vitro, for osteocyte survival and for controlling the expression of osteocytic genes that affect osteoclast and osteoblast function.