In a live mouse, losing menin in bone cells means less bone - and menin overexpression means more
also called osteoblast Men1 knockout bone mass · menin osteoporosis · Men1 osteocyte CXCL10
When menin is deleted from bone-building cells in mice, the mice end up with thinner, weaker bones; when extra menin is put in, they end up with more bone. Deleting it only in the bone cells buried inside the bone also causes osteoporosis, by making the bone-dissolving cells more active.
The same thing, for a scientist
The in-vivo skeletal counterweight, and it is bidirectional, which is rare and strong. OC-Cre;Men1(f/f) mice lacking menin in differentiating osteoblasts show significantly reduced bone mineral density, trabecular bone volume and cortical thickness, with reduced osteoblast and osteoclast number and mineral apposition rate, increased osteocyte number, and primary calvarial osteoblasts that proliferate faster but mineralise poorly with deficient ALP activity. Conversely, Col1a1-driven human menin overexpression in osteoblasts **increases** bone mass, osteoblast number and mineral apposition rate [E1]. A separate group, deleting menin in the osteoblast/osteocyte compartment, found osteoporosis driven by increased osteoclast number and bone resorption, persisting when deletion was restricted to **osteocytes**, via soluble mediators including CXCL10 whose neutralisation reduced osteoclastogenesis [E2].
Why this is the strongest single skeletal argument against chronic menin inhibition in children
Most of the evidence in this beat is one-directional: remove menin, see a phenotype. 1 is bidirectional in the same tissue by the same group - less menin, less bone; more menin, more bone - which is the design that best excludes a nonspecific effect. Two independent laboratories, two different Cre drivers, two different mechanistic routes (osteoblast-autonomous mineral apposition failure; osteocyte-derived CXCL10 driving osteoclastogenesis), arriving at the same organ-level outcome: low bone mass 12.
The population that receives menin inhibitors under the paediatric indication - infants and young children with leukaemia - is already at high risk of low bone mass from corticosteroids, methotrexate, immobilisation and, for many, transplant. A drug-induced osteoblast-lineage menin deficit would be additive on that, and it would be invisible during treatment because nobody measures bone density.
Note the direction against the in-vitro maturation result
In vitro, stable menin inactivation in committed MC3T3-E1 osteoblasts accelerates mineralisation and raises ALP [see mechanism-menin-has-opposite-jobs-at-two-stages-of-the-osteoblast]. In vivo, osteoblast Men1 deletion gives deficient mineral apposition and low ALP activity in primary calvarial osteoblasts 1. These disagree, and the in-vivo result should be given more weight for a whole-organism prediction. The disagreement is recorded here rather than resolved, because it is a real conflict in the literature and the reader should see it.
What would connect it to the drug
Nothing has. A raw PubMed search on 2026-09-19 for any menin-inhibitor term co-occurring with growth plate, chondrocyte, bone mass, osteoblast or puberty in title or abstract returns zero records, against 118 records for 'menin inhibitor'. The revumenib growth-plate finding sits in a toxicology summary with no mechanistic study behind it in the public literature, and the osteoblast menin literature has never been applied to it.
| kind | toxicity |
|---|---|
| severity | unknown in humans; in mice, reduced BMD, trabecular volume and cortical thickness, and osteoporosis from osteocyte-restricted deletion |
| mitigation | DXA and bone-age at baseline, end of treatment and in survivorship follow-up; currently collected in no menin-inhibitor trial |
| tissue | osteoblast and osteocyte |
| direction bidirectional | true |
affects
[ "drug-revumenib", "drug-ziftomenib", "drug-bleximenib" ]
- Low bone mass from menin inhibition would add to the corticosteroid, methotrexate and transplant burden that already reduces bone density in this exact population.
- The effect is bidirectional in mice, which means it is a dose-responsive pharmacology rather than a threshold toxicity, so even partial occupancy should produce partial bone loss.
- Peak bone mass is accrued in childhood and adolescence and cannot be recovered later; a reversible drug effect on an irreversible developmental window is not reversible in the way the beat's reversibility argument assumes.
- Does any child treated with a menin inhibitor have a DXA measurement before and after? If any single centre does, it is the first human bone data in this class.
- Do the two mouse mechanisms - osteoblast mineral-apposition failure and osteocyte CXCL10-driven resorption - both operate under pharmacological rather than genetic menin loss?
- Is CXCL10 measurable in serum on treatment, and would it serve as a non-invasive marker of skeletal target engagement?
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Conditional Men1 deletion in mature osteoblasts reduces bone mineral density, trabecular bone volume, cortical thickness and mineral apposition rate, while osteoblast menin overexpression increases bone mass.
Osteoblast menin regulates bone mass in vivo. · Kanazawa I, Canaff L, Abi Rafeh J, Angrula A, Li J, Riddle RC, et al. · Journal of Biological Chemistry 2015What this evidence cannot show
Mouse; OC-Cre acts in mature osteoblasts so earlier lineage stages are unaffected; the overexpression arm uses human menin cDNA driven by a 2.3-kb Col1a1 promoter, a supraphysiological construct; no growth-plate or longitudinal-growth measurement reported.
Evidence that argues against this (1)
- In vitro, stable menin inactivation in committed osteoblasts accelerates mineralisation and raises ALP - the opposite direction to the in-vivo mineral apposition deficit reported here. Naito J et al. 2005
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Menin deletion in the osteoblast/osteocyte lineage causes osteoporosis via increased osteoclast number and resorption, persisting with osteocyte-restricted deletion, mediated partly by CXCL10.
Loss of menin in osteoblast lineage affects osteocyte-osteoclast crosstalk causing osteoporosis. · Liu P, Lee S, Knoll J, Rauch A, Ostermay S, Luther J, et al. · Cell Death and Differentiation 2017What this evidence cannot show
Mouse; the CXCL10 contribution is shown by neutralising antibody in vitro; osteoblast differentiation and bone formation rate were preserved in this model, which differs from E1.
Evidence that argues against this (1)
- This model preserved osteoblast differentiation and bone formation rate, whereas E1 found both reduced, so the two laboratories disagree on mechanism even while agreeing on the low-bone-mass outcome. Kanazawa I et al. 2015
a second route to the same organ
In vivo, osteoblast Men1 deletion gives DEFICIENT mineral apposition and low ALP, the opposite of the in-vitro maturation acceleration; the conflict is recorded, not resolved
A drug-induced osteoblast menin deficit would be additive on the corticosteroid, methotrexate and transplant bone burden this population already carries