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Updated: Aug 3, 2025
Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
Protein kinase D3 conditional knockout impairs osteoclast formation and increases trabecular bone volume in male mice
Samuel D Burciaga1, Flavia Saavedra1, Lori Fischer1
1Department of Diagnostic & Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, MN 55455, USA.
Abstract:
Studies using kinase inhibitors have shown that the protein kinase D (PRKD) family of serine/threonine kinases are required for formation and function of osteoclasts in culture. However, the involvement of individual protein kinase D genes and their in vivo significance to skeletal dynamics remains unclear. In the current study we present data indicating that protein kinase D3 is the primary form of PRKD expressed in osteoclasts. We hypothesized that loss of PRKD3 would impair osteoclast formation, thereby decreasing bone resorption and increasing bone mass. Conditional knockout (cKO) of Prkd3 using a murine Cre/Lox system driven by cFms-Cre revealed that its loss in osteoclast-lineage cells reduced osteoclast differentiation and resorptive function in culture. Examination of the Prkd3 cKO mice showed that bone parameters were unaffected in the femur at 4 weeks of age, but consistent with our hypothesis, Prkd3 conditional knockout resulted in 18 % increased trabecular bone mass in male mice at 12 weeks and a similar increase at 6 months. These effects were not observed in female mice. As a further test of our hypothesis, we asked if Prkd3 cKO could protect against bone loss in a ligature-induced periodontal disease model but did not see any reduction in bone destruction in this system. Together, our data indicate that PRKD3 promotes osteoclastogenesis both in vitro and in vivo.
Insights
Protein kinase D3 (PRKD3) is crucial for osteoclast formation and function. Its absence in mice leads to increased bone mass, particularly in males, highlighting PRKD3
Area of Science:
- Bone biology and skeletal dynamics.
- Cellular and molecular mechanisms of osteoclastogenesis.
- Serine/threonine kinase signaling in bone metabolism.
Background:
- Kinase inhibitors suggest the protein kinase D (PRKD) family is vital for osteoclast formation and function.
- The specific roles of individual PRKD genes in vivo and their impact on skeletal dynamics are not fully understood.
- Protein kinase D3 (PRKD3) is identified as the predominant PRKD isoform in osteoclasts.
Purpose of the Study:
- To investigate the in vivo role of Protein kinase D3 (PRKD3) in osteoclast formation and bone mass regulation.
- To determine if the loss of PRKD3 affects osteoclast differentiation and resorptive capacity.
- To assess the impact of PRKD3 deficiency on skeletal parameters and bone loss models.
Main Methods:
- Utilized a conditional knockout (cKO) mouse model targeting Prkd3 in osteoclast-lineage cells (cFms-Cre driver).
- Evaluated osteoclast differentiation and resorptive function in vitro.
- Analyzed bone parameters (trabecular bone mass) in Prkd3 cKO mice at various ages (4 weeks, 12 weeks, 6 months).
- Assessed the effect of Prkd3 cKO in a ligature-induced periodontal disease model.
Main Results:
- Loss of PRKD3 in osteoclast-lineage cells reduced osteoclast differentiation and resorptive function in vitro.
- Prkd3 cKO mice showed no significant changes in femur bone parameters at 4 weeks.
- Male Prkd3 cKO mice exhibited an 18% increase in trabecular bone mass at 12 weeks and 6 months.
- No significant increase in bone mass was observed in female Prkd3 cKO mice.
- Prkd3 cKO did not protect against bone destruction in a ligature-induced periodontal disease model.
Conclusions:
- PRKD3 is the primary PRKD isoform involved in osteoclastogenesis.
- PRKD3 promotes osteoclast formation and function both in vitro and in vivo.
- PRKD3 deficiency leads to increased bone mass in male mice, suggesting a sex-specific role in bone regulation.
- PRKD3's role in pathological bone loss, such as in periodontal disease, requires further investigation.
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