Sex-specific hormonal rescue of bone growth in PAPPA2-deficient mice : a role for cannabinoid receptors and STAT3

Recombinant human (rh) insulin-like growth factor-1 (IGF1) treatment has been shown to restore growth velocity and height in children harbouring pregnancy-associated plasma protein-A2 (PAPP-A2) mutations. The present study aimed to evaluate whether pharmacological modulation of the growth hormone (GH)/IGF1 system elicits sex-specific improvements in bone growth in a pappalysin 2 (Pappa2)-deficient mouse model of growth impairment, and to identify the associated signalling pathways.

Pappa2 knockout (Pappa2^ko/ko) mice of both sexes received daily treatment with rhGH, rhIGF1, or rhPAPP-A2 from postnatal day (PND) 5 to PND 35. The IGF1 system, bone remodelling factors, cannabinoid receptors, and intracellular signalling were analyzed in bone.

At the onset of puberty, hormone-treated knockout Pappa2 (Pappa2^ko/ko) mice exhibited increased body length and weight, along with a higher femur weight-to-length ratio following rhGH or rhPAPP-A2 administration. In Pappa2^ko/ko females, hormone treatments reduced the bone resorption marker osteopontin, particularly following rhPAPP-A2, which also led to decreased expression of cannabinoid receptors (CNR1, CNR2, and GPR55). Compared to rhGH, both rhPAPP-A2 and rhIGF1 specifically decreased the IGF binding protein Igfbp5 and increased expression of the bone formation markers osteocalcin and collagen I in females. These effects were accompanied by elevated levels of phosphorylated signal transducer and activator of transcription 3 (STAT3). Pappa2 deficiency and hormone therapy were associated with numerous sex-specific differences in bone IGF1 binding, bone remodelling, cannabinoid receptors, and signal transducer and activator of transcription 3 (STAT3) signalling.

These findings support rhPAPP-A2 as a promising therapeutic candidate for mitigating postnatal bone growth retardation by increasing bone formation and reducing resorption through cannabinoid receptor modulation in a female-specific manner.