Regulatory Effect of Osteocytes on Extramedullary and Bone Marrow Adipose Tissue Development and Function.

PURPOSE OF REVIEW: This review summarizes evidence on osteocyte support of extramedullary and bone marrow adipocyte development and discusses the role of endogenous osteocyte activities of nuclear receptors peroxisome proliferator-activated receptor gamma (PPARG) and alpha (PPARA) in this support. RECENT FINDINGS: PPARG and PPARA proteins, key regulators of glucose and fatty acid metabolism, are highly expressed in osteocytes. They play significant roles in the regulation of osteocyte secretome and osteocyte bioenergetics; both activities contributing to the levels of systemic energy metabolism in part through an effect on metabolic function of extramedullary and bone marrow adipocytes. The PPARs-controlled osteocyte endocrine/paracrine activities, including sclerostin expression, directly regulate adipocyte function, while the PPARs-controlled osteocyte fuel utilization and oxidative phosphorylation contribute to the skeletal demands for glucose and fatty acids, whose availability is under the control of adipocytes. Bone is an inherent element of systemic energy metabolism with PPAR nuclear receptors regulating osteocyte-adipocyte metabolic axes.

Diabetes increases risk of lumbar spinal fusion complications: association with altered structure of newly formed bone at the fusion site.

Diabetes predisposes to spine degenerative diseases often requiring surgical intervention. However, the statistics on the prevalence of spinal fusion success and clinical indications leading to the revision surgery in diabetes are conflicting. The purpose of the presented retrospective observational study was to determine the link between diabetes and lumbar spinal fusion complications using a database of patients (n = 552, 45% male, age 54 ± 13.7 years) residing in the same community and receiving care at the same health care facility. Outcome measures included clinical indications and calculated risk ratio (RR) for revision surgery in diabetes. Paravertebral tissue recovered from a non-union site of diabetic and nondiabetic patients was analyzed for microstructure of newly formed bone. Diabetes increased the RR for revision surgery due to non-union complications (2.80; 95% CI, 1.12-7.02) and degenerative processes in adjacent spine segments (2.26; 95% CI, 1.45-3.53). In diabetes, a risk of revision surgery exceeded the RR for primary spinal fusion surgery by 44% (2.36 [95% CI, 1.58-3.52] vs 1.64 [95% CI, 1.16-2.31]), which was already 2-fold higher than diabetes prevalence in the studied community. Micro-CT of bony fragments found in the paravertebral tissue harvested during revision surgery revealed structural differences suggesting that newly formed bone in diabetic patients may be of compromised quality, as compared with that in nondiabetic patients. In conclusion, diabetes significantly increases the risk of unsuccessful lumbar spine fusion outcome requiring revision surgery. Diabetes predisposes to the degeneration of adjacent spine segments and pseudoarthrosis at the fusion sites, and affects the structure of newly formed bone needed to stabilize fusion.

PPARG in osteocytes controls cell bioenergetics and systemic energy metabolism independently of sclerostin levels in circulation.

Objective: The skeleton is one of the largest organs in the body, wherein metabolism is integrated with systemic energy metabolism. However, the bioenergetic programming of osteocytes, the most abundant bone cells coordinating bone metabolism, is not well defined. Here, using a mouse model with partial penetration of an osteocyte-specific PPARG deletion, we demonstrate that PPARG controls osteocyte bioenergetics and their contribution to systemic energy metabolism independently of circulating sclerostin levels. Methods: In vivo and in vitro models of osteocyte-specific PPARG deletion, i.e. Dmp 1 Cre Pparγ flfl male and female mice (γOT KO ) and MLO-Y4 osteocyte-like cells with either siRNA-silenced or CRISPR/Cas9-edited Pparγ . As applicable, the models were analyzed for levels of energy metabolism, glucose metabolism, and metabolic profile of extramedullary adipose tissue, as well as the osteocyte transcriptome, mitochondrial function, bioenergetics, insulin signaling, and oxidative stress. Results: Circulating sclerostin levels of γOT KO male and female mice were not different from control mice. Male γOT KO mice exhibited a high energy phenotype characterized by increased respiration, heat production, locomotion and food intake. This high energy phenotype in males did not correlate with "beiging" of peripheral adipose depots. However, both sexes showed a trend for reduced fat mass and apparent insulin resistance without changes in glucose tolerance, which correlated with decreased osteocytic responsiveness to insulin measured by AKT activation. The transcriptome of osteocytes isolated from γOT KO males suggested profound changes in cellular metabolism, fuel transport and usage, mitochondria dysfunction, insulin signaling and increased oxidative stress. In MLO-Y4 osteocytes, PPARG deficiency correlated with highly active mitochondria, increased ATP production, shifts in fuel utilization, and accumulation of reactive oxygen species (ROS). Conclusions: PPARG in male osteocytes acts as a molecular break on mitochondrial function, and protection against oxidative stress and ROS accumulation. It also regulates osteocyte insulin signaling and fuel usage to produce energy. These data provide insight into the connection between osteocyte bioenergetics and their sex-specific contribution to the balance of systemic energy metabolism. These findings support the concept that the skeleton controls systemic energy expenditure via osteocyte metabolism. Highlights: Osteocytes function as a body energostat via their bioenergeticsPPARG protein acts as a "molecular break" of osteocyte mitochondrial activityPPARG deficiency activates TCA cycle, oxidative stress and ROS accumulationPPARG controls osteocyte insulin signaling and fuel utilization.

PPARG in osteocytes controls cell bioenergetics and systemic energy metabolism independently of sclerostin levels in circulation.

OBJECTIVE: The skeleton is one of the largest organs in the body, wherein metabolism is integrated with systemic energy metabolism. However, the bioenergetic programming of osteocytes, the most abundant bone cells coordinating bone metabolism, is not well defined. Here, using a mouse model with partial penetration of an osteocyte-specific PPARG deletion, we demonstrate that PPARG controls osteocyte bioenergetics and their contribution to systemic energy metabolism independently of circulating sclerostin levels, which were previously correlated with metabolic status of extramedullary fat depots. METHODS: In vivo and in vitro models of osteocyte-specific PPARG deletion, i.e. Dmp1CrePparγflfl male and female mice (γOTKO) and MLO-Y4 osteocyte-like cells with either siRNA-silenced or CRISPR/Cas9-edited Pparγ. As applicable, the models were analyzed for levels of energy metabolism, glucose metabolism, and metabolic profile of extramedullary adipose tissue, as well as the osteocyte transcriptome, mitochondrial function, bioenergetics, insulin signaling, and oxidative stress. RESULTS: Circulating sclerostin levels of γOTKO male and female mice were not different from control mice. Male γOTKO mice exhibited a high energy phenotype characterized by increased respiration, heat production, locomotion and food intake. This high energy phenotype in males did not correlate with "beiging" of peripheral adipose depots. However, both sexes showed a trend for reduced fat mass and apparent insulin resistance without changes in glucose tolerance, which correlated with decreased osteocytic responsiveness to insulin measured by AKT activation. The transcriptome of osteocytes isolated from γOTKO males suggested profound changes in cellular metabolism, fuel transport, mitochondria dysfunction, insulin signaling and increased oxidative stress. In MLO-Y4 osteocytes, PPARG deficiency correlated with highly active mitochondria, increased ATP production, and accumulation of reactive oxygen species (ROS). CONCLUSIONS: PPARG in male osteocytes acts as a molecular break on mitochondrial function, and protection against oxidative stress and ROS accumulation. It also regulates osteocyte insulin signaling and fuel usage to produce energy. These data provide insight into the connection between osteocyte bioenergetics and their sex-specific contribution to the balance of systemic energy metabolism. These findings support the concept that the skeleton controls systemic energy expenditure via osteocyte metabolism.