Pre-osteoblast-derived Metrnl inhibits osteogenesis, with its systemic knockout increasing trabecular bone mass in mice.
Background
Current therapies for osteoporosis (OP) primarily target osteoclastic bone resorption, leaving a critical gap for anabolic strategies that directly stimulate bone formation. Meteorin-like (Metrnl), a recently identified adipokine, has an undefined and controversial role in bone metabolism. Understanding Metrnl's precise function and mechanism in skeletal biology could uncover novel targets for anabolic bone therapies, addressing the unmet need for treatments that promote new bone growth rather than just preventing loss.
Study Design
Researchers employed an integrated approach, combining clinical bone marrow specimen analysis, proteomics, single-cell RNA sequencing, and conditional genetic ablation mouse models. Skeletal phenotypes were rigorously evaluated using Micro-CT and bone histomorphometry. Intracellular molecular interactions were determined via co-immunoprecipitation and transcriptional activity assays. Mouse models included systemic knockout of Metrnl (n = 6 per group), as well as osteoblast-specific (Ocn-Cre) and osteoprogenitor-specific (Prx1-Cre) conditional knockout mice (n = 6 per group) to pinpoint cell-autonomous effects.
Results
Clinically, Metrnl expression was significantly diminished in bone marrow samples from postmenopausal women with osteoporosis, suggesting its potential relevance to human disease. In mice, Metrnl was predominantly expressed in osteoprogenitor cells, with its expression progressively declining with age. Unexpectedly, systemic knockout of Metrnl resulted in a marked increase in trabecular bone mass, evidenced by a bone volume to total volume ratio (BV/TV) of 4.11 ± 0.08% versus 3.89 ± 0.12% in controls (p < 0.01). This was accompanied by an increased bone formation rate (BFR/BS) of 0.50 ± 0.03 versus 0.38 ± 0.03 μm/day*100 (p < 0.05), without affecting osteoclast activity. This anabolic phenotype was fully recapitulated in osteoblast-specific (Ocn-Cre) and osteoprogenitor-specific (Prx1-Cre) conditional knockout mice, which both exhibited significantly higher BV/TV (4.13 ± 0.06% and 4.04 ± 0.05%, respectively) compared to controls (3.88 ± 0.08%; p < 0.001 and p < 0.01, respectively).
Key Findings
- Metrnl expression was significantly diminished in bone marrow of postmenopausal women with osteoporosis.
- Systemic knockout of Metrnl increased trabecular bone mass (
BV/TV) by 5.6% (p < 0.01) in mice. - Metrnl knockout increased bone formation rate (
BFR/BS) by 31.6% (p < 0.05) without affecting osteoclast activity. - Osteoblast-specific and osteoprogenitor-specific Metrnl knockout also increased
BV/TV(p < 0.001 and p < 0.01 respectively). - Intracellular Metrnl directly interacts with the scaffold protein R, inhibiting osteogenesis.
Why It Matters
This study fundamentally shifts our understanding of Metrnl's role in bone metabolism, identifying it as an inhibitor of osteogenesis rather than a promoter. Targeting Metrnl for inhibition could represent a novel anabolic strategy for treating osteoporosis, moving beyond current anti-resorptive approaches. The finding that Metrnl's expression is diminished in human osteoporotic bone marrow further strengthens its clinical relevance, suggesting that restoring or mimicking its inhibition could be therapeutic. While this is preclinical data, it opens a new avenue for drug development, potentially leading to compounds that enhance bone formation by modulating Metrnl activity, offering a much-needed alternative for patients with severe bone loss.
metrnl
osteoporosis
osteogenesis
bone-formation
adipokine
preclinical-animal