Homozygous deletion of Mitogen Activated Protein Kinase Phosphatase‐1 (MKP‐1) in mice results in gender specific differences in osteoblast gene expression and parathyroid hormone response

Parathyroid hormone (PTH) signals via PTH‐1 receptor (PTH1R) and involves Mitogen Activated Protein Kinase (MAPK) pathways. MAPK phosphatase‐1 (MKP‐1) can dephosphorylate and inactivate MAPKs. Whether MKP‐1 plays a role in PTH1R anabolic action in bone is yet to be investigated. We showed increased and decreased bone mass in MKP‐1 knockout (KO) male and female mice respectively. To examine the molecular mechanism, primary calvarial osteoblasts were isolated from male and female MKP‐1 KO and wild type (WT) mice via sequential collagenase digestion and differentiated with ascorbic acid and b‐glycerophosphate. Osteoblast differentiation was measured by alkaline phosphatase (ALKP), osteocalcin (OCN), cyclin D1, and JunB expression from d3‐21, analyzed by real time PCR, and by ALKP activity and von‐Kossa assay for mineralization. ALKP expression decreased from d3‐15 in WT cultures but stayed on from d5‐21 in cultures from KO mice. PTH stimulated ALKP only in WT osteoblasts. Expression of OCN, cyclin D1, and JunB, showed a biphasic pattern in male KO mice compared to WT or female KO with or without PTH. Von‐Kossa assay showed increased and decreased mineralization in cultures from male and female KO mice respectively, with disparate PTH response. The impact of MKP‐1 deletion on bone mass, osteoblast gene expression and mineralization suggests MKP‐1 as a target gene in the treatment of osteoporosis. Funding NIDDK