Pyk2-Deletion Leads to Female-Specific Femoral Bone Gain Without Affecting Jawbone.

Objectives: Bone loss accelerates with aging and affects women more than men due to estrogen loss. Antiresorptive therapies are common treatments for osteoporosis but can affect maxilla and mandible, leading to osteonecrosis of the jaw. Therefore, novel therapies to preserve bone mass with better safety profiles are needed. The proline tyrosine kinase-2 (Pyk2) acts decreasing osteoblast activity and increasing osteoclast resorption. Consistent with this, it was reported that global deletion of (Pyk2-KO) increases bone mass in female mice. We also reported that estrogen stimulates Pyk2-KO osteoblast activity. However, male mice have not been investigated. Furthermore, the effects of Pyk2 deletion on jawbone have not been elucidated. We hypothesized that Pyk2 deletion will lead to sex-specific bone phenotypes in femoral, maxillary, and mandibular bones.
Methods: Micro-CT analysis of the femur versus maxillae/mandibles of 16-week-old female and male Pyk2-KO mice and littermate (WT) were performed. T-test were performed for significance by sex between Pyk2-KO and WT at the different bone sites (n=5/6 mice/group; p<0.05).
Results: Pyk2-KO female femurs showed statistically higher femoral bone volume/tissue volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th) and reduced trabecular spacing (Tb.Sp) compared to WT females. However, maxillae and mandibles of Pyk2-KO females showed no significant differences in bone density compared to the WT females, suggesting the female bone gain was site specific. In contrast to females, Pyk2-KO males showed no difference in BV/TV in femurs or mandibles, with maxillae showing slightly decreased BV/TV, compared to WT males.
Conclusions: The major findings of this study are that Pyk2 deletion leads to female-specific bone gain localized to femoral bone, without effects on female maxillary or mandibular bones. Targeting Pyk2 may offer a novel strategy for treating bone loss diseases in females, potentially avoiding the negative oral sequalae of current antiresorptive therapies. Supported by Grant No. 1R01AR080076.