The maternal skeleton experiences significant bone loss during lactation, followed by rapid restoration post weaning. Parathyroid-related protein (PTHrP)-induced acidification of the perilacunar matrix by osteocytes is crucial in this process, yet its mechanism remains unclear. Here, we identify Cx43 hemichannels (HCs) as key mediators of osteocyte acidification and perilacunar-canalicular remodeling (PLR). Utilizing transgenic mouse models expressing dominant-negative Cx43 mutants, we show that mice with impaired Cx43 HCs exhibit attenuated lactation-induced responses compared to wild-type and only gap junction-impaired groups, including lacunar enlargement, upregulation of PLR genes, and bone loss with compromised mechanical properties. Furthermore, inhibition of HCs by a Cx43 antibody blunts PTHrP-induced calcium influx and protein kinase A activation, followed by impaired osteocyte acidification. Additionally, impeded HCs suppress bone recovery during the post-lactation period. Our findings highlight the pivotal role of Cx43 HCs in orchestrating dynamic bone changes during lactation and recovery by regulating acidification and remodeling enzyme expression.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11318086PMC
http://dx.doi.org/10.1016/j.celrep.2024.114363DOI Listing

Publication Analysis

Top Keywords

osteocyte acidification
12
acidification perilacunar-canalicular
8
perilacunar-canalicular remodeling
8
bone loss
8
cx43 hcs
8
acidification
5
cx43
5
hcs
5
connexin hemichannels
4
hemichannels drive
4

Similar Publications

Article Synopsis
  • Osteocytes, which are bone cells embedded in small cavities (lacunae) and connected through tiny channels (canaliculi), show structural abnormalities in mice with X-linked hypophosphatemia due to low vitamin D levels; treatment with vitamin D or specific antibodies can improve this condition.
  • Mice lacking the vitamin D receptor in osteocytes or certain phosphate transporters exhibit poor canalicular organization, indicating that the specific actions of vitamin D and phosphate are crucial for maintaining the structural integrity of the lacuno-canalicular network.
  • The study highlights that NFATc1, a protein essential for bone resorption, plays a significant role in mediating the effects of vitamin D and phosphate on the remodeling of the lacuno-c
View Article and Find Full Text PDF

The maternal skeleton experiences significant bone loss during lactation, followed by rapid restoration post weaning. Parathyroid-related protein (PTHrP)-induced acidification of the perilacunar matrix by osteocytes is crucial in this process, yet its mechanism remains unclear. Here, we identify Cx43 hemichannels (HCs) as key mediators of osteocyte acidification and perilacunar-canalicular remodeling (PLR).

View Article and Find Full Text PDF

Osteocytes sense the microenvironmental stimuli, including mechanical stress, and regulate bone resorption by osteoclasts and bone formation by osteoblasts. Diabetes and cancer metastasis to bone raise l-lactic acid in the bone tissue, causing acidification. Here, we investigated the effects of l-lactic acid and extracellular acidification on the function of mouse Ocy454 osteocytes.

View Article and Find Full Text PDF

The physiological role of calcitonin, and its receptor, the CTR (or Calcr), has long been debated. We previously provided the first evidence for a physiological role of the CTR to limit maternal bone loss during lactation in mice by a direct action on osteocytes to inhibit osteocytic osteolysis. We now extend these findings to show that CTR gene expression is upregulated two- to three-fold in whole bone of control mice at the end of pregnancy (E18) and lactation (P21) compared to virgin controls.

View Article and Find Full Text PDF

Measuring cellular metabolism accurately is necessary to understand bioenergetic pathways in cells. The major ATP generating pathways in cells are oxidative phosphorylation and glycolysis. We have recently analyzed and published bioenergetic pathways active in osteoblasts undergoing differentiation in response to various substrates.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!