# Uncovering the dual anabolic and anti-catabolic effects of Pyk2 inhibition on bone mass

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $500,756

## Abstract

SUMMARY. Bone loss is accelerated in menopausal women, and more generally in both men and women with
aging. Current anti-resorptive and osteoanabolic therapies are generally prescribed only after pronounced bone
loss, and all can have adverse clinical effects. Dual-acting agents that are both osteoanabolic and anti-resorptive
may offer novel approaches to increase bone mass. The Pyk2 tyrosine kinase is dual-acting, both decreasing
osteoblast (OB) activity and increasing osteoclast (OC) resorption. Despite a similar increase in cortical
microarchitecture in male and female Pyk2-/- mice, only females exhibit increased cancellous bone mass and
mechanical properties, suggesting sex-specific differences in tissue level properties. In preliminary studies, we
found that ovariectomized Pyk2-/- female mice supplemented with 17β-estradiol (E2) have additively higher bone
mass than WT, and that ulnar loaded Pyk2-/- males (females not tested) exhibit higher bone formation rate,
suggesting enhanced osteogenic responses in vivo. Pyk2-/- OBs have enhanced mineralizing activity in vitro,
which is further stimulated by 17β-estradiol (E2) and raloxifene, a clinically-approved selective estrogen receptor
modulator (SERM). Pyk2-/- OBs exhibit reduced levels of estrogen receptor, ERα, due to its ubiquitin-proteasome
degradation, and we found that ERβ antagonists prevent the E2-stimulated increase in Pyk2-/- OB activity,
suggesting an increase in E2-ERβ signaling. On the other hand, Pyk2-/- OCs exhibit defective OC resorption
activity, and in the presence of E2, OC formation and survival are reduced compared to WT OCs. Our Specific
Aims will test the hypothesis that Pyk2 acts via distinct E2-ERα/ERβ-regulated mechanisms to exert dual-
modulating effects that repress OB activity and promote OC resorption. In Aim 1, we will demonstrate the role
of Pyk2 in the anabolic versus catabolic arms of the bone remodeling cycle by examining 4-, 12- and 21-month
mice in which Pyk2-deletion is targeted to either OBs with collagen type 1a, 2.3-Cre (Pyk2Col2.3) or mature OCs
with cathepsin K-Cre (Pyk2CatK). In addition, Pyk2Col2.3 mice will be subject to tibial anabolic loading, while Pyk2CatK
mice will be examined after hindlimb unloading-induced bone loss. In Aim 2, we will determine if bone mass is
preserved after sex steroid depletion (gonadectomy) of 4-month male/female Pyk2Col2.3 mice (due to elevated
osteogenesis) and Pyk2CatK mice (due to reduced resorption), and if E2 or raloxifene will additively improve bone
mass. We will dissect the Pyk2 mechanisms that regulate ERα degradation/stability, and effects on ERα/ERβ
dimerization, and E2-ERβ signaling in OBs and OBs in vitro. In Aim 3, we will establish the non-inferiority of a
Pyk2-selective inhibitor in preventing/reversing age-associated decline of bone mass and mechanical properties
in 12-month C57BL/6 female mice, compared to a broad-acting inhibitor of focal adhesion kinases, and
raloxifene. Clinical translational impact ...

## Key facts

- **NIH application ID:** 10522662
- **Project number:** 1R01AR080076-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Angela Bruzzaniti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $500,756
- **Award type:** 1
- **Project period:** 2022-08-22 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522662

## Citation

> US National Institutes of Health, RePORTER application 10522662, Uncovering the dual anabolic and anti-catabolic effects of Pyk2 inhibition on bone mass (1R01AR080076-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10522662. Licensed CC0.

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