The longstanding interest of our laboratory is to understand the molecular, cellular and genetic basis of bone remodeling and skeletal homeostasis in animal models and humans and their regulation in health and disease. In addition to primary cells and cell lines, we extensively use mouse genetics and models of human diseases or conditions, in particular osteoporosis and lactation, but also rare diseases, and models of fracture repair and bone regeneration.
Our areas of interest and current projects can be subdivided into the following groups:
- Wnt signaling and bone
As clearly shown for the Wnt signaling pathway, the study of rare genetic disorders of the skeleton can yield insights that fuel novel therapeutic approaches for the treatment of both rare disorders and common skeletal ailments. Wnt signaling is one of the most important developmental signaling pathways that controls cell fate decisions and tissue homeostasis. Not surprisingly, the last decade has provided abundant data implicating the Wnt pathway in bone development and in the regulation of bone mass. Indeed, rare human mutations together with gain- and loss-of- function approaches in mice, have clearly demonstrated that flaws in this pathway lead to altered bone development and mass. Collectively, these discoveries have led to the development of novel therapeutic biologics for the treatment of severe osteoporosis by blocking an endogenous Wnt inhibitor, sclerostin. Dr. Baron has personally been engaged in characterizing the role and the mechanisms by which Wnt signaling affects skeletal biology and bone homeostasis for many years, indeed from the original observation (Gong et al. 2001) that mutations in the main co-receptor for the canonical Wnt signaling affects bone accrual. Dr. Baron has continued to contribute to this field since then with important papers, leading to being invited by Nature Medicine to write a review article on the topic and to other reviews and book chapters (Baron and Gori). More recent work from our lab, including the work on the role of Wnt16 in skeletal homeostasis published on Nature Medicine and reviewed in BoneKey Reports is of great interest, in that it established that trabecular and cortical bone are differentially regulated. In addition, our most recent work on Sfrp4, a WNT signaling inhibitor, and skeletal homeostasis published in the New England Journal of Medicine and PNAS strengthen the hypothesis of a differential regulation of these two bone compartments by Wnt signaling. In the lab, we have several cell lines and mouse models to investigate the role played by several components of the Wnt pathway in the regulation of skeletal homeostasis. Ongoing studies on the role of WNT signaling in skeletal homeostasis, craniofacial development and bone regeneration are part of the current focus of the lab. In this context, Dr. Gori, has been recently awarded a NIH-NIDCR R01 grant for her study entitled “Biology of cortical bone of long bones and calvarium: Role of Sfrp4 in periosteal bone formation.” The goals of these studies are to define the role of Sfrp4, an endogenous Wnt antagonist, on the periosteal surface of the cortex. We hypothesize that Sfrp4 expressed in a discreet pool of periosteal progenitors influences periosteal stem/progenitor cell activities in cortical bone and contributes to their bone regenerative potential and to their response to anabolic drugs.
2) Osteocytes, and in particular their ability to resorb the matrix that surrounds them, and their role in the regulation of bone remodeling and mineral metabolism.
Osteocytes, the most abundant cells in bone, live in a unique environment, embedded into bone and in intimate contact with the bone matrix. Of particular interest is the fact that these cells are the source of two key regulators of bone remodeling: sclerostin, the inhibitor of Wnt signaling and RANKL, both of which are now targeted by antibodies to treat osteoporosis in the clinic. These cells are also the main cells responsible for mechanosensitivity, the mechanism by which the skeleton adapts to gravity and mechanical loading. As such, osteocytes have a crucial role in the regulation of skeletal homeostasis, as we and others have shown (Wein et al. 2014, Wein et al. 2016, Saini et al., Fulzele et al., Komaba et al., Lotinun et al., Kim et al.). Interestingly, and albeit the subject of intense debates for more that 50 years, osteocytes can resorb their peri-lacunar matrix, thereby enlarging the lacunae (osteocytic osteolysis) or secrete new matrix that later mineralizes (perilacunar apposition), thereby reducing the lacuna area. These changes occur in response to various local or systemic cues such as loading/unloading, lactation, estrogen deprivation, PTH and PTHrP signaling or glucocorticoid treatment. Recently, we have reported that preventing matrix degradation by osteocytes impeded osteolysis and prevented the induction of osteoclast differentiation. Furthermore, this also prevented the mobilization of calcium from bone in lactating mice, creating an end-organ resistance despite high levels of PTH and PTHrP (Lotinun et al.). Several projects, using different mouse models with specific deletion of specific genes involved in bone matrix biology in osteocytes are currently underway to explore the link between the matrix that surrounds the osteocytes and the way in which they regulate bone remodeling and calcium and phosphate metabolism.
3) Mechanisms by which PTH/PTHrP signaling regulates skeletal homeostasis.
PTH, together with PTHRP and with sclerostin antibodies, is an anabolic drug, i.e. a drug that increases bone formation, for osteoporosis, a widespread chronic condition linked to aging with important health and socio-economic consequences. Aging and/or estrogen deficiency induce a concomitant decrease in Bone formation (BFR) and an increase in bone marrow adipose tissue (BMAT), suggesting a clinically relevant link between the regulation of BFR and BMAT. Whether the presence of fat in the bone marrow microenvironment exerts negative influences on bone formation and skeletal homeostasis is unclear. Osteoblasts (OBs) and adipocytes (ADs) share a common precursor in the mesenchymal stem cell (MSC) lineage, such that the changes in bone marrow ADs could be directly linked and inversely related to the changes in OB differentiation. We have shown that in addition to decreasing bone mass, deletion of the PTH receptor in the MSC lineage induces an accumulation of BMAT and that PTH treatment in animal models and in humans represses BMAT (Fan et al.). We have identified a novel PTH signaling cascade that involves several transcription factors known to play an important role in the control of osteoblast and adipocyte differentiation: Zfp521, an anti-adipogenic factor that favors BFR, and Zfp423 and Zfp467, proadipogenic factors repressed by PTH and by Zfp521 (Correa et al., Kang et al. Addison et al., Kiviranta et al.,Hesse et al.). Current investigations in the lab are focused on understanding the molecular mechanisms by which PTH increases BFR and represses BMAT. In addition, Zfp467 is playing an important role in osteocytes to transcriptionally activate sclerostin expression and inhibit Wnt signaling, contributing via the osteocyte to the regulation of BMAT. These studies are part of two NIH/NIAMS R01 grants to Dr. Baron entitled: Mechanism of action of PTH: new signaling components that regulate bone formation and bone marrow fat” which investigate whether preventing bone marrow fat will favor bone formation in response to PTH treatment and “PTH resistance and marrow adipogenesis”, which explore the mechanism whereby intermittent parathyroid hormone (PTH) increases bone mass, particularly in older individuals where marrow adiposity is prevalent.