Selective deletion of the soluble Colony-Stimulating Factor 1 isoform in vivo prevents estrogen-deficiency bone loss in mice

Abstract

Neutralizing CSF1 in vivo completely prevents ovariectomy (OVX)-induced bone loss in mice. There are two isoforms of CSF1, soluble (sCSF1), and membrane-bound (mCSF1), but their individual biological functions are unclear. It had been previously reported that mCSF1 knockout (K/O) and wild type (Wt) female mice experience the same degree of bone loss following OVX. In Wt mice the expression of sCSF1 was elevated fourfold in skeletal tissue following OVX while expression of mCSF1 was unchanged. To examine the role of sCSF1 in OVX-induced bone loss, mice were engineered in which sCSF1 was not expressed but expression of mCSF1 was unaffected (sCSF1 K/O). Isoform-specific reverse transcription PCR confirmed the absence of transcripts for sCSF1 in bone tissue isolated from these animals and no circulating CSF1 was detected by ELISA. Surprisingly, there were no significant differences in bone mineral density (BMD) between sCSF1 K/O mice and Wt controls as assessed by dual-energy X-ray absorptiometry and micro-CT. However, one month after OVX, femoral, spinal and total BMD had declined by 11.2%, 8.9%, and 8.7% respectively in OVX-Wt animals as compared to Sham-OVX. In contrast OVX sCSF1 K/O mice showed changes of +0.1%, −2.4%, and +2.3% at the same 3 sites compared to Sham-OVX sCSF1 K/O mice. These data indicate important non-redundant functions for the two isoforms of CSF1 and suggest that sCSF1, but not mCSF1, plays a key role in estrogen-deficiency bone loss.

Bone physiology: Colony-stimulating factor in estrogen-induced bone loss

Only one of the two forms of colony-stimulating factor 1 (CSF1) plays a role in estrogen-deficiency bone loss. CSF1, a protein responsible for white cell proliferation, is required for the development of cells that break down bone tissue. The two forms of CSF1 are soluble (sCSF1) and membrane-bound. A team headed by Gang-Qing Yao at Yale University School of Medicine, New Haven, USA, investigated the relative importance of these forms in mediating bone breakdown. The authors examined the role of sCSF1 in bone loss induced by estrogen deficiency (through ovary removal) in mice. Mice in which sCSF1 expression was blocked but membrane-bound CSF1 unaffected showed no bone loss, indicating that sCSF1 plays a key role in estrogen-deficiency bone loss. Coupled with work by other groups reporting a role for sCSF1 in inflammatory arthritis, the current work suggests that sCSF may be involved in several skeletal disorders.

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