# Role of Complement in Commensal Microbiota Actions Regulating Sketal Maturation

> **NIH VA IK2** · RALPH H JOHNSON VA MEDICAL CENTER · 2022 · —

## Abstract

Abstract
 Commensal microbiota critically regulates osteoimmune processes mediating post-pubertal skeletal
development. Our studies have shown that the commensal gut microbiota suppresses osteoblastic bone-
forming cells and enhances osteoclastic bone-resorbing cells, which impairs bone mass accrual. However,
mechanisms discerning commensal microbiota effects on bone across the lifespan are unclear.
 The study of osteoimmunology has shown that immune cells in the bone marrow regulate bone
modeling/remodeling. Despite knowledge that the commensal gut microbiota directs crosstalk with host
immunity, immune mechanistic studies elucidating the commensal gut microbiota immunomodulatory effects on
skeletal maturation are unclear. Preliminary findings from the investigator’s postdoctoral research work suggest
that commensal microbiota-host interactions stimulate complement signaling to have system catabolic effects in
the maturing skeleton in health and disease.
 Complement signaling protects the host from infection and modulates the immune response, highlighting
the role of complement in maintaining a homeostatic relationship with the commensal microbiota. Our
preliminary data demonstrated that the commensal microbiota upregulates circulating complement
anaphylatoxin C3a, which has also been implicated in inflammatory bowel pathogenesis. Complement receptor
C3aR is expressed on both osteoblasts and osteoclasts, implying that C3a may be a critical regulator of
commensal microbiota effects on the maturing skeleton in health and disease. Three specific aims will address
critical in vivo and in vitro studies utilizing transgenic mice deleting C3aR in both osteoblasts and osteoclasts in
health and under dextran sodium sulfate (DSS)-induced colitis. These three aims will investigate the overall
hypothesis that the commensal gut microbiota upregulation of C3a regulates C3aR derived skeletal maturation
in health and disease throughout the lifespan. Aim 1 will elucidate the role of commensal gut microbiota on
C3aR-mediated osteoblastogenesis in skeletal maturation and deterioration under normal and inflammatory
bowel conditions. Aim 2 will examine commensal gut microbiota actions on C3aR-osteoclastogenic signaling in
the maturing and aging skeleton in health and disease. Aim 3 will determine whether probiotic administration
regulates C3a/C3aR signaling during post-pubertal skeletal development. Elucidating the relationship between
C3/C3aR signaling, the gut microbiota, and bone will provide opportunities for therapeutic interventions to
optimize bone mass accrual in young service members and protect against skeletal deterioration in aging
Veterans.
 This research seeks to define osteoimmunological processes regulating peak bone mass accrual to
withstand either age-related and/or disease-related skeletal deterioration. These studies will innovatively use
bone cells specific C3aR knockdown models to determine microbiota derived complement signaling effects on
ske...

## Key facts

- **NIH application ID:** 10486262
- **Project number:** 1IK2BX005813-01A1
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Jessica Diann Hathaway-Schrader
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10486262

## Citation

> US National Institutes of Health, RePORTER application 10486262, Role of Complement in Commensal Microbiota Actions Regulating Sketal Maturation (1IK2BX005813-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10486262. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*