Co-Treatment With rhBMP-2 and Rapamycin Modulates Osteogenesis-Adipogenesis Balance to Enhance Aged Bone Regeneration.

rhBMP-2 exacerbates the imbalance between osteogenesis and adipogenesis in senescent bone marrow stromal cells (BMSCs), resulting in excess adipocyte accumulation and a diminished osteogenic response.

• Senescent BMSCs treated with rhBMP-2 showed increased adipogenic differentiation compared to non-senescent BMSCs treated with rhBMP-2.
• The osteogenic response to rhBMP-2 was diminished in senescent BMSCs relative to young BMSCs.
• This osteogenesis-adipogenesis imbalance was identified as a key mechanism underlying impaired bone regeneration in aged subjects.
• The finding challenges the assumption that rhBMP-2 retains full osteoinductive efficacy in aged tissue environments.

Excess adipocytes (eADs) within the aged microenvironment contribute to impaired bone regeneration by promoting BMSC senescence and suppressing osteogenic differentiation.

• eADs accumulating in the aged bone microenvironment were shown to have a paracrine or contact-dependent effect on surrounding BMSCs.
• Exposure to eADs increased markers of cellular senescence in BMSCs.
• Osteogenic differentiation capacity of BMSCs was suppressed following exposure to eADs.
• These findings establish eADs as active contributors to, rather than mere bystanders in, age-related bone repair deficits.

A novel energy-supplying hydrogel system designated PBR (PEGSN-PGA/rhBMP-2/Rapa) was designed for local minimally invasive treatment of aged bone defects.

• The hydrogel system incorporates PEGSN-PGA as the scaffold material combined with rhBMP-2 and rapamycin (Rapa).
• The system was described as suitable for the aged regenerative microenvironment with excellent bone integration performance.
• The hydrogel was designed for minimally invasive local delivery to bone defect sites.
• The energy-supplying design was intended to support the metabolic needs of senescent cells in the aged microenvironment.

The PBR hydrogel system effectively regulated abnormal differentiation of senescent BMSCs, maintained the cell cycle process, and retained regenerative potential in the senescent microenvironment.

• Co-treatment with rhBMP-2 and rapamycin shifted the differentiation balance of senescent BMSCs toward osteogenesis and away from adipogenesis.
• Cell cycle progression in senescent BMSCs was maintained under PBR treatment.
• The regenerative potential of senescent BMSCs for bone repair was preserved by the PBR system.
• Rapamycin's role as an mTOR inhibitor was implicated in modulating the senescence-associated differentiation imbalance.

The study presents a novel strategy for treatment of rhBMP-2-mediated bone degenerative diseases by targeting the interplay among adipogenesis, cellular senescence, and bone regeneration during aging.

• The approach addresses a previously underappreciated consequence of rhBMP-2 use in aged patients, namely promotion of adipogenesis in senescent BMSCs.
• Rapamycin co-delivery was identified as a feasible approach to counteract senescence-driven differentiation imbalance.
• The study offers a perspective connecting adipogenic excess, cellular senescence, and diminished osteogenic capacity as an integrated pathological axis.
• The findings have potential clinical implications for elderly patients receiving rhBMP-2-based therapies for bone repair.