# Osteoclastic Regulation of Local Bone Formation

> **NIH VA I01** · VA LOMA LINDA HEALTHCARE SYSTEM · 2024 · —

## Abstract

The healing of ~10% of several million traumatic or nontraumatic fractures occurring annually in the US is
delayed or impaired resulting in nonunion or delayed union. The annual cost for their treatment and management
exceeds $20 billion, leading to considerable healthcare costs and human suffering. A good understanding of the
mechanism of fracture healing is critical for the development and proper use of novel and effective therapies.
Fracture healing is a complex and dynamic process with osteoclasts and osteoblasts playing indispensable roles.
The critical core of fracture healing is the callus remodeling, which is initiated with resorption of the cartilaginous
callus followed by the coupled formation of bony callus that subsequently is remodeled to cortical bone
indistinguishable from the native bone. The osteoclastic regulation of the local coupled bone formation is in part
mediated through local release of osteoclastic soluble osteoanabolic factors and is an integral regulatory
mechanism of callus remodeling. This study tests two specific hypotheses that are relevant to the osteoclastic
regulation of local bone formation/regeneration: Hypothesis 1. Local injections of osteoclastic microvesicles (MV)
into fractures accelerates the healing of skeletal fractures by accelerating fracture callus formation and
remodeling. This hypothesis is supported by the following preliminary findings: 1) osteoclasts released soluble
MV that have pro-osteogenic, pro-chondrogenic, and pro-angiogenic activities, 2) injections of osteoclastic MV
at the surface of calvaria stimulated local bone formation, and 3) injections of MV into fractures promoted neo-
angiogenesis in fracture callus and accelerated fracture healing. Hypothesis 2. EfnB2 is a key osteoanabolic
component of osteoclastic MV and is in part responsible for the osteoanabolic actions of osteoclastic MV.
Accordingly, a review of current literature and the following preliminary data suggest that EfnB2 is an attractive
candidate of an osteoanabolic component of osteoclastic MV: 1) osteoclastic MV contains appreciable amounts
of EfnB2, 2) pretreatment of MV with anti-EfnB2 antibody abrogated its osteogenic activity, 3) EfnB2-deficient
MV had reduced osteogenic and fracture healing activities, whereas MV from osteoclasts overexpressing EfnB2
showed greater osteoanabolic activity, 4) pretreatment of osteoprogenitors with anti-EphB4 antibody prevented
osteoclastic MV to exert its osteogenic activity. Aim 1 tests Hypothesis 1 by using a simple transverse femoral
fracture model to determine: a) an optimal injection regimen for osteoclastic MV by determining the duration-of-
stay of the MV after local injection at fracture site, optimal injection frequency, duration between injections, and
optimal dose range; b) if an optimized injection regimen of osteoclastic MV would accelerate bony bridging of
fracture gaps and increase torsional mechanical strength of fractured bones in male as well as female mice; and
c)...

## Key facts

- **NIH application ID:** 10805232
- **Project number:** 1I01BX006038-01A2
- **Recipient organization:** VA LOMA LINDA HEALTHCARE SYSTEM
- **Principal Investigator:** Kin-Hing William Lau
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10805232

## Citation

> US National Institutes of Health, RePORTER application 10805232, Osteoclastic Regulation of Local Bone Formation (1I01BX006038-01A2). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10805232. Licensed CC0.

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