Maternal endocrine function is a fundamental determinant for perinatal health¹. Although the skeleton is increasingly recognized as an endocrine organ, the contribution of osteocytes, the most abundant type of bone cells², to maternal hormonal regulation during pregnancy and lactation remains incompletely understood. Recently, we identified cystic fibrosis transmembrane conductance regulator (CFTR), originally known as an epithelial Cl^– channel, to be functionally expressed in osteocytes and required for skeletal integrity³. In the present study, we hypothesized that osteocytic CFTR might be important to bone endocrine function for maternal-offspring regulation and perinatal health.

We used an osteocyte-specific CFTR knockout mouse model (cKO, Dmp1-Cre; Cftr^fl/fl) in comparison with Cre-negative (Ctrl, Cftr^fl/f) controls. In a breeding model using cKO females crossed with wild-type males, offspring born to osteocytic CFTR-deficient mothers showed significantly reduced (P< 0.05) body weight (3.12 ± 0.07g, n = 49) on day 7 post birth as compared to those (3.93 ± 0.07g, n = 30) born to control mothers. The survival rate of the pups from cKO mothers in three weeks post birth was significantly lower than those from control mothers (n = 5-7 litters). In the survived pups, the body weight gained in three weeks was substantially lower in the cKO group (n = 5-7 litters), which together suggested early development defects in offspring born to cKO mothers. To identify the underlying mechanism, we examined the maternal bone phenotype. Adult female cKO mice displayed marked bone loss, including reduced bone mass and trabecular bone sparsity as revealed by micro-CT analysis. Osteocalcin (OCN), a key osteocyte-derived hormone implicated in metabolic and developmental regulation, was significantly decreased in osteocytes of cKO mice (n = 6). Serum OCN and Ca²⁺ levels were found to rise during lactation period in control mothers, which was largely abolished in cKO mice. Consistently in an osteocyte model (MLO-Y4), CFTR knockout led to suppression of OCN at both mRNA and protein levels. Transcriptomic analysis of the osteocyte model further revealed broad changes in additional osteocyte-secreted factors (e.g., Bmp1), indicating that CFTR controls a wider osteocyte endocrine network beyond OCN alone. Moreover, patch-clamp, fluorescence-based Cl^–– and pH-imaging revealed defective Cl^– transport and impaired cAMP-evoked Cl^–-dependent H⁺ secretion in MLO-Y4 cells with CFTR knockout, which may underlie the dysregulated endocrine function in CFTR knockout osteocytes.

Taken together, these findings have shown that CFTR deficiency in maternal osteocytes causes skeletal deterioration and disrupts the bone endocrine program, particularly OCN production, thereby weakening maternal endocrine support during the perinatal period for offspring early development, revealing a new mechanism for maternal bone-to-offspring regulatory axis.