PTHrP regulates the modeling of cortical bone surfaces at fibrous insertion sites during growth

Abstract

The sites that receive ligament and tendon insertions (entheses) on the cortical surfaces of long bones are poorly understood, particularly as regards modeling and regulation. Entheses are classified as either fibrocartilagenous or fibrous based on their structures. Fibrous entheses typically insert into the metaphysis or diaphysis of a long bone, bear a periosteal component, and are modeled during long bone growth. This modeling forms a root system by which the insertions attach to the cortical surface. In the case of the medial collateral ligament, modeling drives actual migration of the ligament along the cortical surface in order to accommodate linear growth, whereas in other sites modeling may excavate a deep cortical root system (e.g., the teres major insertion) or a shallow root system with a large footprint (e.g., the latissimus dorsi insertion). We report here that conditionally deleting parathyroid hormone-related protein (PTHrP) in fibrous entheses via Scleraxis-Cre targeting causes modeling to fail in these three iterations of osteoclast-driven enthesis excavation or migration. These iterations appear to represent formes frusts of a common modeling strategy, presumably differing from each other as a consequence of differences in biomechanical control. In sites in which PTHrP is not induced, either physiologically or because of conditional deletion, modeling does not take place and fibrocartilage is induced. These findings represent the initial genetic evidence that PTHrP regulates periosteal/intramembranous bone cell activity on cortical bone surfaces and indicate that PTHrP serves as a load-induced modeling tool in fibrous insertion sites during linear growth.

Bone microarchitecture at muscle attachment sites: The relationship between macroscopic scores of entheses and their cortical and trabecular microstructural design

“…Many bone ridges are formed through the endochondral ossification pathway; however, considering the large variability in the morphology of bone ridges, it is not known whether they all develop in the same way (Blitz et al, 2009a;Schweitzer et al, 2010). There is some evidence from animal studies that fibrous entheses are formed postnatally and that parathyroid hormonerelated protein (PTHrP) is an essential regulator of their development (Wang et al, 2013); PTHrP is used as a "load-induced modeling tool that directs osteoclasts to excavate the root system by which these sites attach to the cortical surface" (Chen et al, 2007;Wang et al, 2013). We are just beginning to understand the development of entheses, and many questions regarding these processes are still unanswered (Schweitzer et al, 2010).…”

“…Specifically, in order to profoundly understand the relevance of macroscopic scoring of entheses (in the form of entheseal changes), we have to understand several more issues which are important for stress transfer, such as: different histological types of entheses (Currey, 2002;Schlecht, 2012b), the angle of muscle attachment to the bone surface and the pennation angle (Alexander and Vernon, 1975;Thomopoulos et al, 2007), the skeletal region where the enthesis is located, the movement of the enthesis location during growth, caused by constant resorption and new deposition (Hoyte and Enlow, 1966;Wang et al, 2013), the difference in body size, and the embryological development of the entheses. Although differences in body size may also be important for entheseal morphology, we observed in our sample that an individual can present different macroscopic stages at different insertion sites even on the same bone.…”

Enthesis fibrocartilage cells originate from a population of Hedgehog-responsive cells modulated by the loading environment

“…This specialized tissue limits stress concentrations that arise at the interface between the two mechanically disparate materials via gradients in structure and composition (Lu and Thomopoulos, 2013;Thomopoulos et al, 2010). Entheses are broadly classified into two groups based on their morphology (Benjamin et al, 2002;Wang et al, 2013).…”

“…Recently, factors associated with the Hh pathway have been localized to various entheses. PTHrP is widely expressed in numerous fibrous entheses and deletion of PTHrP results in bony outgrowths (Wang et al, 2013). Additionally, expression levels of this molecule depend on the loading environment (Chen et al, 2007;Wang et al, 2013).…”

“…PTHrP is widely expressed in numerous fibrous entheses and deletion of PTHrP results in bony outgrowths (Wang et al, 2013). Additionally, expression levels of this molecule depend on the loading environment (Chen et al, 2007;Wang et al, 2013). Expression of Gli1, a transcriptional effector and a direct target gene of all Hh proteins, has also been identified in fibrocartilagenous entheses (Blitz et al, 2009;Liu et al, 2012).…”