Abstract
Mechanical stimulation of the skeleton promotes bone gain and suppresses bone loss, ultimately resulting in improved bone strength and fracture resistance. The molecular mechanisms directing anabolic and/or anti-catabolic actions on the skeleton during loading are not fully understood. Identifying molecular mechanisms of mechanotransduction (MTD) signaling cascades could identify new therapeutic targets. Most research into MTD mechanisms is typically focused on understanding the signaling pathways that stimulate new bone formation in response to load. However, we investigated the structural, signaling and transcriptional molecules that suppress the stimulatory effects of loading. The high bone mass phenotype of mice with global deletion of either Pyk2 or Src suggests a role for these tyrosine kinases in repression of bone formation. We used fluid shear stress as a MTD stimulus to identify a novel Pyk2/Src-mediated MTD pathway that represses mechanically-induced bone formation. Our results suggest Pyk2 and Src function as molecular switches that inhibit MTD in our mechanically stimulated osteocyte culture experiments. Once activated by oscillatory fluid shear stress (OFSS), Pyk2 and Src translocate to and accumulate in the nucleus, where they associate with a protein involved in DNA methylation and the interpretation of DNA methylation patterns –methyl-CpG-binding domain protein 2 (MBD2). OFSS-induced Cox-2 and osteopontin expression was enhanced in Pyk2 KO osteoblasts, while inhibition of Src enhanced osteocalcin expression in response to OFSS. We found that Src kinase activity increased in the nucleus of osteocytes in response to OFSS and an interaction activated between Src (Y418) and Pyk2 (Y402) increased in response to OFSS. Thus, as a mechanism to prevent an over-reaction to physical stimulation, mechanical loading may induce the formation of a Src/Pyk2/MBD2 complex in the nucleus that functions to suppress anabolic gene expression.
Highlights
Pyk2 plays an important role in bone remodeling. [1,2,3,4,5]
To determine if Pyk2 plays a role in regulating other anabolic genes in response to oscillatory fluid shear stress (OFSS), relative expression of osteopontin (OPN) mRNA was examined in Pyk2 KO osteoblasts
We suggest that Pyk2 and Src may serve as an ‘‘off switch’’ to suppress the anabolic response of bone subjected to mechanical load
Summary
Pyk plays an important role in bone remodeling. [1,2,3,4,5]. Pyk null mice exhibit increased bone mass. [1,6]. Pyk plays an important role in bone remodeling. Pyk null mice exhibit increased bone mass. Reports differ on the explanation of the osteopetrotic phenotype of the Pyk knockout mouse. Once group reports the phenotype results from defective osteoclast function implicating Pyk2’s role in osteclast driven bone resporption, while another group contends increased osteoblast differentiation contributes to the osteopetrosis [7,8]. Pyk2’s more well-known family member, FAK, serves as an important positive regulator of mechanical stimuli in osteoblasts [9]. Pyk2’s role in mediating the response of bone cells to mechanotransduction is unknown, but is suggested to be different than FAK’s [10]. Src phosphorylates both FAK and Pyk, while FAK and Pyk associate and phosphorylate Src [11,12,13,14]
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